Objective： The aim of the study was to observe the expressions of genes related to genome stability and DNA repair in the members of nasopharyngeal carcinoma （NPC） clustedng families. Methods： In the Zhongshan Cit...Objective： The aim of the study was to observe the expressions of genes related to genome stability and DNA repair in the members of nasopharyngeal carcinoma （NPC） clustedng families. Methods： In the Zhongshan City where there is highly incidence rate of NPC, we chose the members of the NPC clustering families as objects, and the patients of nasopharyngitis and NPC as the control group. We isolated the RNA from the nasopharyngeal tissue, and synthesized its cRNA, the genome stability and DNA repair genes chip technique, chemiluminescent detection and real-time fluorescence quantita- tive technique were used to examine the genome stability and DNA repair genes in the nasopharyngeal tissue. Results： More genome stability and DNA repair genes were up-regulated in the members of the NPC clustering families than the NPC patients, and the range of up-regulated was high, with the over up-regulated 100 times genes including TEP1, MSH4, PMS2LI. Fewer genome stability and DNA repair genes were down-regulated in the members of the NPC clustering families than the NPC patients, the ubiquitin genes almost were down-regulated, the results also could be confirmed by real-time fluorescence quantitative PCR. Conclusion： There are specially expression character of genome stability and DNA repair genes in the members of NPC clustering families.展开更多
Rapeseed(Brassica napus,AACC)was formed by hybridization between progenitor species Brassica rapa(AA)and Brassica oleracea(CC).As a result of a limited number of hybridization events between specific progenitor genoty...Rapeseed(Brassica napus,AACC)was formed by hybridization between progenitor species Brassica rapa(AA)and Brassica oleracea(CC).As a result of a limited number of hybridization events between specific progenitor genotypes and strong breeding selection for oil quality traits,rapeseed has limited genetic diversity.The production of resynthesized B.napus lines via interspecific hybridization of the diploid progenitor species B.rapa and B.oleracea is one possible way to increase genetic variation in rapeseed.However,most resynthesized lines produced so far have been reported to be meiotically unstable and infertile,in contrast to established B.napus cultivars.This hinders both maintenance and use of this germplasm in breeding programs.We characterized a large set of 140 resynthesized lines produced by crosses between B.rapa and B.oleracea,as well as between B.rapa and wild C genome species(B.incana,B.hilarionis,B.montana,B.Bourgeaui,B.villosa and B.cretica)for purity(homozygosity),fertility,and genome stability.Self-pollinated seed set,seeds per ten pods as well as percentage pollen viability were used to estimate fertility.SNP genotyping was performed using the Illumina Infinium Brassica 60K array for 116 genotypes,with at least three individuals per line.Most of the material which had been advanced through multiple generations was no longer pure,with heterozygosity detected corresponding to unknown parental contributions via outcrossing.Fertility and genome stability were both genotypedependent.Most lines had high numbers of copy number variants(CNVs),indicative of meiotic instability,and high numbers of CNVs were significantly associated with reduced fertility.Eight putatively stable resynthesized B.napus lines were observed.Further investigation of these lines may reveal the mechanisms underlying this effect.Our results suggest that selection of stable resynthesized lines for breeding purposes is possible.展开更多
Chloroplast or mitochondrial dysfunctions are known to induce global changes at the cellular level.This occurs through the implementation of retrograde responses emanating from the organelles and influencing nuclear g...Chloroplast or mitochondrial dysfunctions are known to induce global changes at the cellular level.This occurs through the implementation of retrograde responses emanating from the organelles and influencing nuclear gene expression.Organellar instability broadly impacts cellular function and frequently leads to defects in cell cycle progression(Figure 1A).展开更多
Activities of the chloroplasts and nucleus are coordinated by retrograde signaling,which play crucial roles in plant development and environmental adaptation.However,the connection between chloroplast status and nucle...Activities of the chloroplasts and nucleus are coordinated by retrograde signaling,which play crucial roles in plant development and environmental adaptation.However,the connection between chloroplast status and nuclear genome stability is poorly understood.Chloroplast state transitions enable the plant to balance photosystem absorption capacity in an environment with changing light quality.Here,we report that abnormal chloroplast state transitions lead to instability in the nuclear genome and impaired plant growth.We observed increased DNA damage in the state transition-defective Arabidopsis thaliana mutant stn7,and demonstrated that this damage was triggered by cytokinin accumulation and activation of cytokinin signaling.We showed that cytokinin signaling promotes a competitive association between ARABIDOPSIS RESPONSE REGULATOR 10(ARR10)with PROLIFERATING CELLULAR NUCLEAR ANTIGEN 1/2(PCNA1/2),inhibiting the binding of PCNA1/2 to nuclear DNA.This affects DNA replication,leading to replicationdependent genome instability.Treatment with 2,5-dibromo-3-methyl-6-isopropylbenzoquinone that simulates the reduction of the plastoquinone pool during abnormal state transitions increased the accumulation of ARABIDOPSIS HISTIDINE-CONTAINING PHOSPHOTRANSMITTER 1,a phosphotransfer protein involved in cytokinin signaling,and promoted the interaction between ARR10 with PCNA1/2,leading to increased DNA damage.These findings highlight the function of cytokinin signaling in coordinating chloroplast function and nuclear genome integrity during plant acclimation to environmental changes.展开更多
Allopolyploids often exhibit advantages in vigor and adaptability compared to diploids.A long-term goal in the economically important Brassica genus has been to develop a new allohexaploid crop type(AABBCC)by combinin...Allopolyploids often exhibit advantages in vigor and adaptability compared to diploids.A long-term goal in the economically important Brassica genus has been to develop a new allohexaploid crop type(AABBCC)by combining different diploid and allotetraploid crop species.However,early-generation allohexaploids often face challenges like unstable meiosis and low fertility,and the phenotypic performance of these synthetic lines has rarely been assessed.This study analyzes agronomic traits,fertility,and genome stability in ArArBcBcCcCc lines derived from four crosses between B.carinata and B.rapa after 9–11 selfing generations.Our results demonstrate polyploid advantage in vigor and seed traits,considerable phenotypic variation,and high fertility and genome stability.Meanwhile,parental genotypes significantly influence outcomes in advanced allohexaploids.Structural variants,largely resulting from A–C homoeologous exchanges,contribute to genomic variation and influence hexaploid genome stability,with the A sub-genome showing the highest variability.Both positive and negative impacts of SVs on fertility and seed weight are observed.Pseudo-euploids,frequently appearing,do not significantly affect fertility or other agronomic traits compared to euploids,indicating a potential pathway toward a stable allohexaploid species.These findings provide insights into the challenge and potential for developing an adaptable and stable Brassica hexaploid through selection.展开更多
We are very pleased to announce a special issue, to be published in June, 2016, on ＂Genome Stability＂ in the journal Genomics, Proteomies ＆ Bioinformaties （GPB）. This special issue aims to provide a platform for ...We are very pleased to announce a special issue, to be published in June, 2016, on ＂Genome Stability＂ in the journal Genomics, Proteomies ＆ Bioinformaties （GPB）. This special issue aims to provide a platform for specialists or experts in the field to report their results and share their opinions on the topic. We are inviting you to submit high-quality papers to this special issue. The vip editors for this special issue are Dr. Zhao-Qi Wang （The Leibniz Institute on Aging - Fritz Lipmann Institute （FLI）, Germany）, Dr. Xingzbi Xu （Capital Normal University, China）, and Dr. Daochun Kong （Peking University, China）.展开更多
While Mek1/2 and Gsk3βinhibition("2i")supports the maintenance of murine embryonic stem cells(EsCs)in a homogenous naive state,prolonged culture in 2i results in aneuploidy and DNA hypomethylation that impa...While Mek1/2 and Gsk3βinhibition("2i")supports the maintenance of murine embryonic stem cells(EsCs)in a homogenous naive state,prolonged culture in 2i results in aneuploidy and DNA hypomethylation that impairs developmental potential.Additionally,2i fails to support derivation and culture of fully potent female ESCs.Here we find that mouse ESCs cultured in 2i/LIF supplemented with lipid-rich albumin(AlbuMAx)undergo pluripotency transition yet maintain genomic stability and full potency over long-term culture.Mechanisticaily,lipids in AlbuMAx impact intracellular metabolism including nucleotide biosynthesis,lipid biogenesis,and TCA cycle intermediates,with enhanced expression of DNMT3s that prevent DNA hypomethylation.Lipids induce a formative-like pluripotent state through direct stimulation of Erk2 phosphorylation,which also alleviates X chromosome loss in female ESCs.Importantly,both male and female"all-ESc"mice can be generated from de novo derived ESCs using AlbuMAXbased media.Our findings underscore the importance of lipids to pluripotency and link nutrient cues to genome integrity in early development.展开更多
Vectored vaccines based on highly attenuated modified vaccinia Ankara(MVA) are reported to be immunogenic, tolerant to pre-existing immunity, and able to accommodate and stably maintain very large transgenes. MVA is u...Vectored vaccines based on highly attenuated modified vaccinia Ankara(MVA) are reported to be immunogenic, tolerant to pre-existing immunity, and able to accommodate and stably maintain very large transgenes. MVA is usually produced on primary chicken embryo fibroblasts, but production processes based on continuous cell lines emerge as increasingly robust and cost-effective alternatives. An isolate of a hitherto undescribed genotype was recovered by passage of a nonplaque-purified preparation of MVA in a continuous anatine suspension cell line(CR.pIX) in chemically defined medium.The novel isolate(MVA-CR19) replicated to higher infectious titers in the extracellular volume of suspension cultures and induced fewer syncytia in adherent cultures. We now extend previous studies with the investigation of the point mutations in structural genes of MVA-CR19 and describe an additional point mutation in a regulatory gene. We furthermore map and discuss an extensive rearrangement of the left telomer of MVA-CR19 that appears to have occurred by duplication of the right telomer. This event caused deletions and duplications of genes that may modulate immunologic properties of MVACR19 as a vaccine vector. Our characterizations also highlight the exceptional genetic stability of plaque-purified MVA:although the phenotype of MVA-CR19 appears to be advantageous for replication, we found that all genetic markers that differentiate wildtype and MVA-CR19 are stably maintained in passages of recombinant viruses based on either wildtype or MVA-CR.展开更多
During cellular proliferation DNA undergoes frequent rep-lication cycles in which errors inevitably accumulate.DNA simultaneously faces continuous damage from endogenous sources[e.g.,reactive oxygen species(ROS)]and e...During cellular proliferation DNA undergoes frequent rep-lication cycles in which errors inevitably accumulate.DNA simultaneously faces continuous damage from endogenous sources[e.g.,reactive oxygen species(ROS)]and environmen-tal stressors,such as ultraviolet(UV)and ionizing radiation(IR).Such lesions compromise genomic stability and may escalate into DNA double-strand breaks(DSBs).Failure to repair DSBs can ultimately trigger cell death1.展开更多
N^(6)-methyladenosine(m^(6)A)in RNA within R-loops plays pivotal roles in transcription regulation and genome stability.However,the precise impacts and distinct mechanisms of m^(6)A on both regulatory and aberrant R-l...N^(6)-methyladenosine(m^(6)A)in RNA within R-loops plays pivotal roles in transcription regulation and genome stability.However,the precise impacts and distinct mechanisms of m^(6)A on both regulatory and aberrant R-loops remain poorly understood.Here,we reveal that METTL3,the nuclear m^(6)A writer,ensures genome integrity by differentially modulating R-loops in a position-and length-dependent manner.In mouse embryonic stem cells(m ESCs),Mettl3 depletion results in impaired cell proliferation and increased cell death due to excessive DNA damage.Notably,Mettl3 knockout reduces the overall abundance of R-loops,with a decrease in broad R-loops and an increase in sharp Rloops.R-loops are diminished near transcription end sites(TESs),leading to transcriptional readthrough of genes with m^(6)A-modified transcripts and potentially contributing to genome instability.Conversely,increased sharp R-loops located in the antisense orientation relative to gene transcription are associated with DNA damage hotspots.These findings unveil a dual regulatory mechanism in which METTL3-m^(6)A orchestrates transcription fidelity and genome stability through distinct R-loop-dependent manners.展开更多
Here, we provide data suggesting that the absence of silencing of the ectopic reprogramming factors used to reprogram somatic cells to induced pluripotent stem cells （iPSCs） may predispose iPSCs to genomic instabili...Here, we provide data suggesting that the absence of silencing of the ectopic reprogramming factors used to reprogram somatic cells to induced pluripotent stem cells （iPSCs） may predispose iPSCs to genomic instability. We encourage stem cell scientists to undertake an extensive characterization and standardization of much larger cohorts of iPSC lines in order to set up rigorous criteria to define safe and stable bonafide iPSCs.展开更多
Liver injury is a major health issue with significant implications for liver function and overall well-being,but precise mechanisms of the N^(6-)methyladenine(m^(6)A)reader YTHDF3 in liver injury remain severely under...Liver injury is a major health issue with significant implications for liver function and overall well-being,but precise mechanisms of the N^(6-)methyladenine(m^(6)A)reader YTHDF3 in liver injury remain severely understudied.Here,we discovered that Ythdf3 knockout exacerbated CCL4-induced liver injury with a reduction in functional hepatocytes and liver stem cells using single cell RNA-sequencing and organoid culture.Furthermore,Mettl14 and YTHDF3-dependent RNA m^(6)A dysregulation induced DNA damage.Moreover,we found YTHDF3 could bind and modulate CCAAT/enhancer-binding protein-alpha(CEBPA)translation in an m^(6)A-dependent manner.Mechanistically,knockout of Ythdf3 impeded the translation of CEBPA,subsequently inhibiting the expression of poly(ADP-ribose)(PAR)polymerase-1(PARP1)and Peroxiredoxin 2(PRDX2).This inhibition promoted DNA damage and genomic instability,ultimately exacerbating liver damage.This work uncovers an essential role of m^(6)A/YTHDF3/CEBPA regulatory axes in governing cell fates and genomic stability,thereby preventing liver injury.Importantly,these findings offer potential therapeutic avenues for targeting YTHDF3 and CEBPA in the treatment of liver injuryrelated diseases.展开更多
DNA double-strand breaks （DSBs） are critical lesions that can result in cell death or a wide variety of genetic alterations including largeor small-scale deletions, loss of heterozygosity, translocations, and chromo...DNA double-strand breaks （DSBs） are critical lesions that can result in cell death or a wide variety of genetic alterations including largeor small-scale deletions, loss of heterozygosity, translocations, and chromosome loss. DSBs are repaired by non-homologous end-joining （NHEJ） and homologous recombination （HR）, and defects in these pathways cause genome instability and promote tumorigenesis. DSBs arise from endogenous sources including reactive oxygen species generated during cellular metabolism, collapsed replication forks, and nucleases, and from exogenous sources including ionizing radiation and chemicals that directly or indirectly damage DNA and are commonly used in cancer therapy. The DSB repair pathways appear to compete for DSBs, but the balance between them differs widely among species, between different cell types of a single species, and during different cell cycle phases of a single cell type. Here we review the regulatory factors that regulate DSB repair by NHEJ and HR in yeast and higher eukaryotes. These factors include regulated expression and phosphorylation of repair proteins, chromatin modulation of repair factor accessibility, and the availability of homologous repair templates. While most DSB repair proteins appear to function exclusively in NHEJ or HR, a number of proteins influence both pathways, including the MRE11/RAD50/NBS1（XRS2） complex, BRCA1, histone H2AX, PARP-1, RAD18, DNA-dependent protein kinase catalytic subunit （DNA-PKcs）, and ATM. DNA-PKcs plays a role in mammalian NHEJ, but it also influences HR through a complex regulatory network that may involve crosstalk with ATM, and the regulation of at least 12 proteins involved in HR that are phosphorylated by DNA-PKcs and/or ATM.展开更多
Homologous recombination （HR） comprises a series of interrelated pathways that function in the repair of DNA double-stranded breaks （DSBs） and interstrand crosslinks （ICLs）. In addition, recombination provides c...Homologous recombination （HR） comprises a series of interrelated pathways that function in the repair of DNA double-stranded breaks （DSBs） and interstrand crosslinks （ICLs）. In addition, recombination provides critical support for DNA replication in the recovery of stalled or broken replication forks, contributing to tolerance of DNA damage. A central core of proteins, most critically the RecA homolog Rad51, catalyzes the key reactions that typify HR： homology search and DNA strand invasion. The diverse functions of recombination are reflected in the need for context-specific factors that perform supplemental functions in conjunction with the core proteins. The inability to properly repair complex DNA damage and resolve DNA replication stress leads to genomic instability and contributes to cancer etiology. Mutations in the BRCA2 recombination gene cause predisposition to breast and ovarian cancer as well as Fanconi anemia, a cancer predisposition syndrome characterized by a defect in the repair of DNA interstrand crosslinks. The cellular functions of recombination are also germane to DNA-based treatment modalities of cancer, which target replicating cells by the direct or indirect induction of DNA lesions that are substrates for recombination pathways. This review focuses on mechanistic aspects of HR relating to DSB and ICL repair as well as replication fork support.展开更多
In their seminal publication describing the structure of the DNA double helix , Watson and Crick wrote what may be one of the greatest understatements in the scientific literature, namely that ＂It has not escaped our...In their seminal publication describing the structure of the DNA double helix , Watson and Crick wrote what may be one of the greatest understatements in the scientific literature, namely that ＂It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.＂ Half a century later, we more fully appreciate what a huge challenge it is to replicate six billion nucleotides with the accuracy needed to stably maintain the human genome over many generations. This challenge is perhaps greater than was realized 50 years ago, because subsequent studies have revealed that the genome can be destabilized not only by environmental stresses that generate a large number and variety of potentially cytotoxic and mutagenic lesions in DNA but also by various sequence motifs of normal DNA that present challenges to replication. Towards a better understanding of the many determinants of genome stability, this chapter reviews the fidelity with which undamaged and damaged DNA is copied, with a focus on the eukaryotic B- and Y-family DNA polymerases, and considers how this fidelity is achieved.展开更多
Maintenance of genome stability is crucial for the survival and reproduction of all organisms.However,various exogenous and endogenous factors frequently induce DNA damage,threatening genome stability.Therefore,all or...Maintenance of genome stability is crucial for the survival and reproduction of all organisms.However,various exogenous and endogenous factors frequently induce DNA damage,threatening genome stability.Therefore,all organisms have evolved complex and sophisticated DNA damage response(DDR)mechanisms including transcription reprogramming,cell cycle arrest,DNA repair,and cell death(Ciccia and Elledge,2010).Compared with the research in mammals and yeasts,the DDR mechanisms in plants are far less well-understood(Herbst et al.,2024).展开更多
Barley(Hordeum vulgare L.)is one of the most Aluminum(Al)sensitive cereal species.In this study,the physiological,biochemical,and molecular response of barley seedlings to Al treatment was examined to gain insight int...Barley(Hordeum vulgare L.)is one of the most Aluminum(Al)sensitive cereal species.In this study,the physiological,biochemical,and molecular response of barley seedlings to Al treatment was examined to gain insight into Al response and tolerance mechanisms.The results showed that superoxide dismutase(SOD),peroxidase(POD)and catalase(CAT)activity were inhibited to different degrees following Al exposure.The MDA content also significantly increased with increasing Al concentrations.SRAP results indicated significant differences between Al treatments and controls in terms of SRAP profile,and the genomic template stability(GTS)decreased with increasing Al concentration and duration.These integrative results help to elucidate the underlying mechanisms that the barley response to Al toxicity.展开更多
The phytohormone abscisic acid （ABA） regulates many aspects of division. Previous study indicates that ABA treatment increases DNA plant growth, including seed germination, root growth and cell damage and somatic ho...The phytohormone abscisic acid （ABA） regulates many aspects of division. Previous study indicates that ABA treatment increases DNA plant growth, including seed germination, root growth and cell damage and somatic homologous recombination （HR） in Arabi- dopsis abo4/pol ε （aba overly-sensitive 4/DNA polymerase ε） mutants. DNA replication factor C （RFC） complex is required for loading PCNA （Proliferating Cell Nuclear Antigen） during DNA replication. The defect in RFC1, the largest subunit of RFC, causes the high HR and DNA damage sensitivity in Arabidopsis. Here we found that like pol e/abo4, rfcl is sensitive to ABA in both ABA-inhibiting seed germination and root growth. However, ABA treatment greatly reduces HR and also reduces the expression of the DNA-damaged marker genes in ,rfcl. These results suggest that RFCI plays critical roles in ABA-mediated HR in Arabidopsis.展开更多
Arsenic(As),one of the most harmful toxicant at the global level,severely affects plant metabolism when taken up.Interestingly,the presence of silicon(Si)as a fertilizer in As-contaminated soil is an effective strateg...Arsenic(As),one of the most harmful toxicant at the global level,severely affects plant metabolism when taken up.Interestingly,the presence of silicon(Si)as a fertilizer in As-contaminated soil is an effective strategy to decrease As accumulation in plants.Brassica juncea(var.Varuna)were grown hydroponically to investigate the role of Si at biochemical and molecular levels under arsenite(As^3+)stress.Seedlings of B.juncea were exposed to As^3+,Si,and a combination of both elements.Our data demonstrated that seedlings exposed to As^3+showed an inhibition in shoot length,chlorophyll,carotenoid,and protein,while co-application of Si improved these growth parameters.Silicon supplementation reduced As accumulation in shoot.Increase/decrease was observed in stress-related parameters(cysteine and proline),antioxidant enzymes(superoxide dismutase,ascorbate peroxidase,and catalase),and oxidative stress markers(malondialdehyde and H2O2),which were improved upon co-application of Si as compared to As^3+alone treatment.Random amplified polymorphic DNA(RAPD)is a suitable biomarker assay for plants for assessing the genotoxicity.Seven RAPD primers produced a total of 39 and 48 bands in the leaves of the untreated and treated seedlings,respectively.The RAPD band-profiles and genomic template stability were consistent with other growth and physiological parameters.In conclusion,the genotoxic alterations along with the biochemical parameters indicate that the exposure to Si mitigates As^3+-induced oxidative stress by improving the stress-related parameters and antioxidant system in B.juncea.展开更多
AIM To evaluate the relation between 12 polymorphisms and the development of gastric cancer(GC) and colorectal cancer(CRC).METHODS In this study,we included 125 individuals with GC diagnosis,66 individuals with CRC di...AIM To evaluate the relation between 12 polymorphisms and the development of gastric cancer(GC) and colorectal cancer(CRC).METHODS In this study,we included 125 individuals with GC diagnosis,66 individuals with CRC diagnosis and 475 cancer-free individuals. All participants resided in the North region of Brazil and authorized the use of their samples. The 12 polymorphisms(in CASP8,CYP2 E1,CYP19 A1,IL1 A,IL4,MDM2,NFKB1,PAR1,TP53,TYMS,UGT1 A1 and XRCC1 genes) were genotyped in a single PCR for each individual,followed by fragment analysis. To avoid misinterpretation due to population substructure,we applied a previously developed set of 61 ancestryinformative markers that can also be genotyped by multiplex PCR. The statistical analyses were performed in Structure v.2.3.4,R environment and SPSS v.20.RESULTS After statistical analyses with the control of confounding factors,such as genetic ancestry,three markers(rs79071878 in IL4,rs3730485 in MDM2 and rs28362491 in NFKB1) were positively associated with the development of GC. One of these markers(rs28362491) and the marker in the UGT1 A1 gene(rs8175347) were positively associated with the development of CRC. Therefore,we investigated whether the joint presence of the deleterious alleles of each marker could affect the development of cancer and we obtained positive results in all analyses. Carriers of the combination of alleles RP1 + DEL(rs79071878 and rs28361491,respectively) are at 10-times greater risk of developing GC than carriers of other combinations. Similarly,carriers of the combination of DEL + RARE(rs283628 and rs8175347) are at about 12-times greater risk of developing CRC than carriers of other combinations.CONCLUSION These findings are important for the comprehension of gastric and CRC development,particularly in highly admixed populations,such as the Brazilian population.展开更多
基金Supported by a grant from the National Natural Science Foundation of China (No.30672713)
文摘Objective： The aim of the study was to observe the expressions of genes related to genome stability and DNA repair in the members of nasopharyngeal carcinoma （NPC） clustedng families. Methods： In the Zhongshan City where there is highly incidence rate of NPC, we chose the members of the NPC clustering families as objects, and the patients of nasopharyngitis and NPC as the control group. We isolated the RNA from the nasopharyngeal tissue, and synthesized its cRNA, the genome stability and DNA repair genes chip technique, chemiluminescent detection and real-time fluorescence quantita- tive technique were used to examine the genome stability and DNA repair genes in the nasopharyngeal tissue. Results： More genome stability and DNA repair genes were up-regulated in the members of the NPC clustering families than the NPC patients, and the range of up-regulated was high, with the over up-regulated 100 times genes including TEP1, MSH4, PMS2LI. Fewer genome stability and DNA repair genes were down-regulated in the members of the NPC clustering families than the NPC patients, the ubiquitin genes almost were down-regulated, the results also could be confirmed by real-time fluorescence quantitative PCR. Conclusion： There are specially expression character of genome stability and DNA repair genes in the members of NPC clustering families.
基金funded by the German Research Council(DFG grant MA6473/2-1,awarded to AM)The Mason lab is partially funded by the Deutsche Forschungsgemeinschaft(DFG,German Research Foundation)under Germany’s Excellence Strategy-EXC 2070-390732324.
文摘Rapeseed(Brassica napus,AACC)was formed by hybridization between progenitor species Brassica rapa(AA)and Brassica oleracea(CC).As a result of a limited number of hybridization events between specific progenitor genotypes and strong breeding selection for oil quality traits,rapeseed has limited genetic diversity.The production of resynthesized B.napus lines via interspecific hybridization of the diploid progenitor species B.rapa and B.oleracea is one possible way to increase genetic variation in rapeseed.However,most resynthesized lines produced so far have been reported to be meiotically unstable and infertile,in contrast to established B.napus cultivars.This hinders both maintenance and use of this germplasm in breeding programs.We characterized a large set of 140 resynthesized lines produced by crosses between B.rapa and B.oleracea,as well as between B.rapa and wild C genome species(B.incana,B.hilarionis,B.montana,B.Bourgeaui,B.villosa and B.cretica)for purity(homozygosity),fertility,and genome stability.Self-pollinated seed set,seeds per ten pods as well as percentage pollen viability were used to estimate fertility.SNP genotyping was performed using the Illumina Infinium Brassica 60K array for 116 genotypes,with at least three individuals per line.Most of the material which had been advanced through multiple generations was no longer pure,with heterozygosity detected corresponding to unknown parental contributions via outcrossing.Fertility and genome stability were both genotypedependent.Most lines had high numbers of copy number variants(CNVs),indicative of meiotic instability,and high numbers of CNVs were significantly associated with reduced fertility.Eight putatively stable resynthesized B.napus lines were observed.Further investigation of these lines may reveal the mechanisms underlying this effect.Our results suggest that selection of stable resynthesized lines for breeding purposes is possible.
基金supported by grants from the Agence Nationale de la Recherche(21-CE20-0027)the University of Strasbourg.
文摘Chloroplast or mitochondrial dysfunctions are known to induce global changes at the cellular level.This occurs through the implementation of retrograde responses emanating from the organelles and influencing nuclear gene expression.Organellar instability broadly impacts cellular function and frequently leads to defects in cell cycle progression(Figure 1A).
基金supported by the National Natural Science Foundation of China(grant no.32322007,32100192,and U22A20446).
文摘Activities of the chloroplasts and nucleus are coordinated by retrograde signaling,which play crucial roles in plant development and environmental adaptation.However,the connection between chloroplast status and nuclear genome stability is poorly understood.Chloroplast state transitions enable the plant to balance photosystem absorption capacity in an environment with changing light quality.Here,we report that abnormal chloroplast state transitions lead to instability in the nuclear genome and impaired plant growth.We observed increased DNA damage in the state transition-defective Arabidopsis thaliana mutant stn7,and demonstrated that this damage was triggered by cytokinin accumulation and activation of cytokinin signaling.We showed that cytokinin signaling promotes a competitive association between ARABIDOPSIS RESPONSE REGULATOR 10(ARR10)with PROLIFERATING CELLULAR NUCLEAR ANTIGEN 1/2(PCNA1/2),inhibiting the binding of PCNA1/2 to nuclear DNA.This affects DNA replication,leading to replicationdependent genome instability.Treatment with 2,5-dibromo-3-methyl-6-isopropylbenzoquinone that simulates the reduction of the plastoquinone pool during abnormal state transitions increased the accumulation of ARABIDOPSIS HISTIDINE-CONTAINING PHOSPHOTRANSMITTER 1,a phosphotransfer protein involved in cytokinin signaling,and promoted the interaction between ARR10 with PCNA1/2,leading to increased DNA damage.These findings highlight the function of cytokinin signaling in coordinating chloroplast function and nuclear genome integrity during plant acclimation to environmental changes.
基金supported by the Sino-German Research Project(GZ 1362)Grains Research and Development Corporation International Visiting Fellowship(UWA2406-010BGX)+1 种基金the National Natural Science Foundation of China(32171982)the Fundamental Research Funds for the Central Universities of the Chinese Government(2662023PY004).
文摘Allopolyploids often exhibit advantages in vigor and adaptability compared to diploids.A long-term goal in the economically important Brassica genus has been to develop a new allohexaploid crop type(AABBCC)by combining different diploid and allotetraploid crop species.However,early-generation allohexaploids often face challenges like unstable meiosis and low fertility,and the phenotypic performance of these synthetic lines has rarely been assessed.This study analyzes agronomic traits,fertility,and genome stability in ArArBcBcCcCc lines derived from four crosses between B.carinata and B.rapa after 9–11 selfing generations.Our results demonstrate polyploid advantage in vigor and seed traits,considerable phenotypic variation,and high fertility and genome stability.Meanwhile,parental genotypes significantly influence outcomes in advanced allohexaploids.Structural variants,largely resulting from A–C homoeologous exchanges,contribute to genomic variation and influence hexaploid genome stability,with the A sub-genome showing the highest variability.Both positive and negative impacts of SVs on fertility and seed weight are observed.Pseudo-euploids,frequently appearing,do not significantly affect fertility or other agronomic traits compared to euploids,indicating a potential pathway toward a stable allohexaploid species.These findings provide insights into the challenge and potential for developing an adaptable and stable Brassica hexaploid through selection.
文摘We are very pleased to announce a special issue, to be published in June, 2016, on ＂Genome Stability＂ in the journal Genomics, Proteomies ＆ Bioinformaties （GPB）. This special issue aims to provide a platform for specialists or experts in the field to report their results and share their opinions on the topic. We are inviting you to submit high-quality papers to this special issue. The vip editors for this special issue are Dr. Zhao-Qi Wang （The Leibniz Institute on Aging - Fritz Lipmann Institute （FLI）, Germany）, Dr. Xingzbi Xu （Capital Normal University, China）, and Dr. Daochun Kong （Peking University, China）.
基金supported by the New York State Stem Cell Science Program under contract C32581GGthe National Institutes of Health under award numbers:1 R01 GM129380-01 and 1R210OD031973-01 (to D.W.).
文摘While Mek1/2 and Gsk3βinhibition("2i")supports the maintenance of murine embryonic stem cells(EsCs)in a homogenous naive state,prolonged culture in 2i results in aneuploidy and DNA hypomethylation that impairs developmental potential.Additionally,2i fails to support derivation and culture of fully potent female ESCs.Here we find that mouse ESCs cultured in 2i/LIF supplemented with lipid-rich albumin(AlbuMAx)undergo pluripotency transition yet maintain genomic stability and full potency over long-term culture.Mechanisticaily,lipids in AlbuMAx impact intracellular metabolism including nucleotide biosynthesis,lipid biogenesis,and TCA cycle intermediates,with enhanced expression of DNMT3s that prevent DNA hypomethylation.Lipids induce a formative-like pluripotent state through direct stimulation of Erk2 phosphorylation,which also alleviates X chromosome loss in female ESCs.Importantly,both male and female"all-ESc"mice can be generated from de novo derived ESCs using AlbuMAXbased media.Our findings underscore the importance of lipids to pluripotency and link nutrient cues to genome integrity in early development.
基金Part of this work was financially supported by the EU FP7 Grant FLUNIVAC(Project-ID 602604).
文摘Vectored vaccines based on highly attenuated modified vaccinia Ankara(MVA) are reported to be immunogenic, tolerant to pre-existing immunity, and able to accommodate and stably maintain very large transgenes. MVA is usually produced on primary chicken embryo fibroblasts, but production processes based on continuous cell lines emerge as increasingly robust and cost-effective alternatives. An isolate of a hitherto undescribed genotype was recovered by passage of a nonplaque-purified preparation of MVA in a continuous anatine suspension cell line(CR.pIX) in chemically defined medium.The novel isolate(MVA-CR19) replicated to higher infectious titers in the extracellular volume of suspension cultures and induced fewer syncytia in adherent cultures. We now extend previous studies with the investigation of the point mutations in structural genes of MVA-CR19 and describe an additional point mutation in a regulatory gene. We furthermore map and discuss an extensive rearrangement of the left telomer of MVA-CR19 that appears to have occurred by duplication of the right telomer. This event caused deletions and duplications of genes that may modulate immunologic properties of MVACR19 as a vaccine vector. Our characterizations also highlight the exceptional genetic stability of plaque-purified MVA:although the phenotype of MVA-CR19 appears to be advantageous for replication, we found that all genetic markers that differentiate wildtype and MVA-CR19 are stably maintained in passages of recombinant viruses based on either wildtype or MVA-CR.
基金supported by grants fromthe Shenzhen Medical Research Fund(Grant No.A2302040).
文摘During cellular proliferation DNA undergoes frequent rep-lication cycles in which errors inevitably accumulate.DNA simultaneously faces continuous damage from endogenous sources[e.g.,reactive oxygen species(ROS)]and environmen-tal stressors,such as ultraviolet(UV)and ionizing radiation(IR).Such lesions compromise genomic stability and may escalate into DNA double-strand breaks(DSBs).Failure to repair DSBs can ultimately trigger cell death1.
基金supported by the National Key Research and Development Program of China(2024YFA1802100)the Strategic Priority Research Program of Chinese Academy of Sciences(XDB0570101)+5 种基金the National Natural Science Foundation of China(32370644,32121001)the National Key Research and Development Program of China(2024YFC3405901,2020YFA0803401)the Key Research Program of Frontier Sciences,Chinese Academy of Sciences(ZDBS-LYSM013)Beijing Natural Science Foundation(L244023)Next-Generation Bioinformatics Algorithms(XDA0460302)CAS Youth Interdisciplinary Team。
文摘N^(6)-methyladenosine(m^(6)A)in RNA within R-loops plays pivotal roles in transcription regulation and genome stability.However,the precise impacts and distinct mechanisms of m^(6)A on both regulatory and aberrant R-loops remain poorly understood.Here,we reveal that METTL3,the nuclear m^(6)A writer,ensures genome integrity by differentially modulating R-loops in a position-and length-dependent manner.In mouse embryonic stem cells(m ESCs),Mettl3 depletion results in impaired cell proliferation and increased cell death due to excessive DNA damage.Notably,Mettl3 knockout reduces the overall abundance of R-loops,with a decrease in broad R-loops and an increase in sharp Rloops.R-loops are diminished near transcription end sites(TESs),leading to transcriptional readthrough of genes with m^(6)A-modified transcripts and potentially contributing to genome instability.Conversely,increased sharp R-loops located in the antisense orientation relative to gene transcription are associated with DNA damage hotspots.These findings unveil a dual regulatory mechanism in which METTL3-m^(6)A orchestrates transcription fidelity and genome stability through distinct R-loop-dependent manners.
文摘Here, we provide data suggesting that the absence of silencing of the ectopic reprogramming factors used to reprogram somatic cells to induced pluripotent stem cells （iPSCs） may predispose iPSCs to genomic instability. We encourage stem cell scientists to undertake an extensive characterization and standardization of much larger cohorts of iPSC lines in order to set up rigorous criteria to define safe and stable bonafide iPSCs.
基金supported by the National Key Research and Development Program of China(2022YFD130040307)the Fundamental Research Funds for the Central Universities(KYCXJC2024001)the National Institute of Mental Health(R01 MH122142,B.C.D.)of the National Institutes of Health(NIH)。
文摘Liver injury is a major health issue with significant implications for liver function and overall well-being,but precise mechanisms of the N^(6-)methyladenine(m^(6)A)reader YTHDF3 in liver injury remain severely understudied.Here,we discovered that Ythdf3 knockout exacerbated CCL4-induced liver injury with a reduction in functional hepatocytes and liver stem cells using single cell RNA-sequencing and organoid culture.Furthermore,Mettl14 and YTHDF3-dependent RNA m^(6)A dysregulation induced DNA damage.Moreover,we found YTHDF3 could bind and modulate CCAAT/enhancer-binding protein-alpha(CEBPA)translation in an m^(6)A-dependent manner.Mechanistically,knockout of Ythdf3 impeded the translation of CEBPA,subsequently inhibiting the expression of poly(ADP-ribose)(PAR)polymerase-1(PARP1)and Peroxiredoxin 2(PRDX2).This inhibition promoted DNA damage and genomic instability,ultimately exacerbating liver damage.This work uncovers an essential role of m^(6)A/YTHDF3/CEBPA regulatory axes in governing cell fates and genomic stability,thereby preventing liver injury.Importantly,these findings offer potential therapeutic avenues for targeting YTHDF3 and CEBPA in the treatment of liver injuryrelated diseases.
文摘DNA double-strand breaks （DSBs） are critical lesions that can result in cell death or a wide variety of genetic alterations including largeor small-scale deletions, loss of heterozygosity, translocations, and chromosome loss. DSBs are repaired by non-homologous end-joining （NHEJ） and homologous recombination （HR）, and defects in these pathways cause genome instability and promote tumorigenesis. DSBs arise from endogenous sources including reactive oxygen species generated during cellular metabolism, collapsed replication forks, and nucleases, and from exogenous sources including ionizing radiation and chemicals that directly or indirectly damage DNA and are commonly used in cancer therapy. The DSB repair pathways appear to compete for DSBs, but the balance between them differs widely among species, between different cell types of a single species, and during different cell cycle phases of a single cell type. Here we review the regulatory factors that regulate DSB repair by NHEJ and HR in yeast and higher eukaryotes. These factors include regulated expression and phosphorylation of repair proteins, chromatin modulation of repair factor accessibility, and the availability of homologous repair templates. While most DSB repair proteins appear to function exclusively in NHEJ or HR, a number of proteins influence both pathways, including the MRE11/RAD50/NBS1（XRS2） complex, BRCA1, histone H2AX, PARP-1, RAD18, DNA-dependent protein kinase catalytic subunit （DNA-PKcs）, and ATM. DNA-PKcs plays a role in mammalian NHEJ, but it also influences HR through a complex regulatory network that may involve crosstalk with ATM, and the regulation of at least 12 proteins involved in HR that are phosphorylated by DNA-PKcs and/or ATM.
文摘Homologous recombination （HR） comprises a series of interrelated pathways that function in the repair of DNA double-stranded breaks （DSBs） and interstrand crosslinks （ICLs）. In addition, recombination provides critical support for DNA replication in the recovery of stalled or broken replication forks, contributing to tolerance of DNA damage. A central core of proteins, most critically the RecA homolog Rad51, catalyzes the key reactions that typify HR： homology search and DNA strand invasion. The diverse functions of recombination are reflected in the need for context-specific factors that perform supplemental functions in conjunction with the core proteins. The inability to properly repair complex DNA damage and resolve DNA replication stress leads to genomic instability and contributes to cancer etiology. Mutations in the BRCA2 recombination gene cause predisposition to breast and ovarian cancer as well as Fanconi anemia, a cancer predisposition syndrome characterized by a defect in the repair of DNA interstrand crosslinks. The cellular functions of recombination are also germane to DNA-based treatment modalities of cancer, which target replicating cells by the direct or indirect induction of DNA lesions that are substrates for recombination pathways. This review focuses on mechanistic aspects of HR relating to DSB and ICL repair as well as replication fork support.
文摘In their seminal publication describing the structure of the DNA double helix , Watson and Crick wrote what may be one of the greatest understatements in the scientific literature, namely that ＂It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.＂ Half a century later, we more fully appreciate what a huge challenge it is to replicate six billion nucleotides with the accuracy needed to stably maintain the human genome over many generations. This challenge is perhaps greater than was realized 50 years ago, because subsequent studies have revealed that the genome can be destabilized not only by environmental stresses that generate a large number and variety of potentially cytotoxic and mutagenic lesions in DNA but also by various sequence motifs of normal DNA that present challenges to replication. Towards a better understanding of the many determinants of genome stability, this chapter reviews the fidelity with which undamaged and damaged DNA is copied, with a focus on the eukaryotic B- and Y-family DNA polymerases, and considers how this fidelity is achieved.
基金supported by the National Natural Science Foundation of China(32270306 and 32070312)HZAU-AGIS Cooperation Fund(SZYJY2022004)Huazhong Agricultural University Scientific&Technological Self-innovation Foundation(2662024PY019).
文摘Maintenance of genome stability is crucial for the survival and reproduction of all organisms.However,various exogenous and endogenous factors frequently induce DNA damage,threatening genome stability.Therefore,all organisms have evolved complex and sophisticated DNA damage response(DDR)mechanisms including transcription reprogramming,cell cycle arrest,DNA repair,and cell death(Ciccia and Elledge,2010).Compared with the research in mammals and yeasts,the DDR mechanisms in plants are far less well-understood(Herbst et al.,2024).
基金This research was funded by National Key Technology Research and Development Program(2015BAD01B02)the National Natural Science Foundation of China(31401316).
文摘Barley(Hordeum vulgare L.)is one of the most Aluminum(Al)sensitive cereal species.In this study,the physiological,biochemical,and molecular response of barley seedlings to Al treatment was examined to gain insight into Al response and tolerance mechanisms.The results showed that superoxide dismutase(SOD),peroxidase(POD)and catalase(CAT)activity were inhibited to different degrees following Al exposure.The MDA content also significantly increased with increasing Al concentrations.SRAP results indicated significant differences between Al treatments and controls in terms of SRAP profile,and the genomic template stability(GTS)decreased with increasing Al concentration and duration.These integrative results help to elucidate the underlying mechanisms that the barley response to Al toxicity.
文摘The phytohormone abscisic acid （ABA） regulates many aspects of division. Previous study indicates that ABA treatment increases DNA plant growth, including seed germination, root growth and cell damage and somatic homologous recombination （HR） in Arabi- dopsis abo4/pol ε （aba overly-sensitive 4/DNA polymerase ε） mutants. DNA replication factor C （RFC） complex is required for loading PCNA （Proliferating Cell Nuclear Antigen） during DNA replication. The defect in RFC1, the largest subunit of RFC, causes the high HR and DNA damage sensitivity in Arabidopsis. Here we found that like pol e/abo4, rfcl is sensitive to ABA in both ABA-inhibiting seed germination and root growth. However, ABA treatment greatly reduces HR and also reduces the expression of the DNA-damaged marker genes in ,rfcl. These results suggest that RFCI plays critical roles in ABA-mediated HR in Arabidopsis.
基金The first author thanks Department of Biotechnology,Government of India for fellowship(No.DBT/JRF/14/AL/250).
文摘Arsenic(As),one of the most harmful toxicant at the global level,severely affects plant metabolism when taken up.Interestingly,the presence of silicon(Si)as a fertilizer in As-contaminated soil is an effective strategy to decrease As accumulation in plants.Brassica juncea(var.Varuna)were grown hydroponically to investigate the role of Si at biochemical and molecular levels under arsenite(As^3+)stress.Seedlings of B.juncea were exposed to As^3+,Si,and a combination of both elements.Our data demonstrated that seedlings exposed to As^3+showed an inhibition in shoot length,chlorophyll,carotenoid,and protein,while co-application of Si improved these growth parameters.Silicon supplementation reduced As accumulation in shoot.Increase/decrease was observed in stress-related parameters(cysteine and proline),antioxidant enzymes(superoxide dismutase,ascorbate peroxidase,and catalase),and oxidative stress markers(malondialdehyde and H2O2),which were improved upon co-application of Si as compared to As^3+alone treatment.Random amplified polymorphic DNA(RAPD)is a suitable biomarker assay for plants for assessing the genotoxicity.Seven RAPD primers produced a total of 39 and 48 bands in the leaves of the untreated and treated seedlings,respectively.The RAPD band-profiles and genomic template stability were consistent with other growth and physiological parameters.In conclusion,the genotoxic alterations along with the biochemical parameters indicate that the exposure to Si mitigates As^3+-induced oxidative stress by improving the stress-related parameters and antioxidant system in B.juncea.
基金Supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico(CNPq)Coordenacao de Aperfeicoamento de Pessoal de Nível Superior(CAPES)Pró-Reitoria de Pesquisa e Pós-Graduacao da Universidade Federal do Pará/Fundacao Amparo e Desenvolvimento da Pesquisa(PROPESP-UFPA/FADESP)
文摘AIM To evaluate the relation between 12 polymorphisms and the development of gastric cancer(GC) and colorectal cancer(CRC).METHODS In this study,we included 125 individuals with GC diagnosis,66 individuals with CRC diagnosis and 475 cancer-free individuals. All participants resided in the North region of Brazil and authorized the use of their samples. The 12 polymorphisms(in CASP8,CYP2 E1,CYP19 A1,IL1 A,IL4,MDM2,NFKB1,PAR1,TP53,TYMS,UGT1 A1 and XRCC1 genes) were genotyped in a single PCR for each individual,followed by fragment analysis. To avoid misinterpretation due to population substructure,we applied a previously developed set of 61 ancestryinformative markers that can also be genotyped by multiplex PCR. The statistical analyses were performed in Structure v.2.3.4,R environment and SPSS v.20.RESULTS After statistical analyses with the control of confounding factors,such as genetic ancestry,three markers(rs79071878 in IL4,rs3730485 in MDM2 and rs28362491 in NFKB1) were positively associated with the development of GC. One of these markers(rs28362491) and the marker in the UGT1 A1 gene(rs8175347) were positively associated with the development of CRC. Therefore,we investigated whether the joint presence of the deleterious alleles of each marker could affect the development of cancer and we obtained positive results in all analyses. Carriers of the combination of alleles RP1 + DEL(rs79071878 and rs28361491,respectively) are at 10-times greater risk of developing GC than carriers of other combinations. Similarly,carriers of the combination of DEL + RARE(rs283628 and rs8175347) are at about 12-times greater risk of developing CRC than carriers of other combinations.CONCLUSION These findings are important for the comprehension of gastric and CRC development,particularly in highly admixed populations,such as the Brazilian population.
