Background： Base excision repair （BER） plays an important role in the maintenance of genome integrity and anticancer drug resistance. This study aimed to explore the role of BER gene polymorphisms in response to ch...Background： Base excision repair （BER） plays an important role in the maintenance of genome integrity and anticancer drug resistance. This study aimed to explore the role of BER gene polymorphisms in response to chemotherapy for advanced non-small cell lung cancer （NSCLC） patients treated with platinum-based chemotherapy. Methods： During the period from November 2009 to January 2016, a total of 152 patients diagnosed with NSCLC Stage IIIB and IV in the First Hospital of Jilin University were admitted into this study. The XRCC1 G28152A, MUTYH G972C, HOGG1 C1245G. and PARPI T2444C polymorphisms of all the patients were detected by mass spectrometry. The logistic regression was used for statictical analysis. All tests were bilateral test, and a P 〈 0.05 was considered statistically significant. Results： The logistic regression model showed that the response rate of chemotherapy of the PARP1 T2444C polymorphisms, CC genotype （odds ratio [OR]： 5.216, 95% confidence interval [CI]： 1.568-17.352, P = 0.007）, TC genotype （OR： 2.692, 95% C1：1.007-7.198, P = 0.048）, as well as the genotype of TC together with CC （OR： 3.178, 95% CI： 1.229-8.219, P = 0.017） were significantly higher than those of TT wild type. There was no relationship between the MUTYH G972C, XRCC1 G28152A, and HOGGI C1245G gene polymorphisms and chemosensitivity. Conclusions： The PARPI 2444 mutation allele C might be associated with the decreased sensitivity to platinum-based chemotherapy in advanced NSCLC. These findings may be helpful in designing individualized cancer treatment.展开更多
Cancer cells,in which the RAS and PI3K pathways are activated,produce high levels of reactive oxygen species(ROS),which cause oxidative DNA damage and ultimately cellular senescence.This process has been documented in...Cancer cells,in which the RAS and PI3K pathways are activated,produce high levels of reactive oxygen species(ROS),which cause oxidative DNA damage and ultimately cellular senescence.This process has been documented in tissue culture,mouse models,and human pre-cancerous lesions.In this context,cellular senescence functions as a tumour suppressor mechanism.Some rare cancer cells,however,manage to adapt to avoid senescence and continue to proliferate.One well-documented mode of adaptation involves increased production of antioxidants often associated with inactivation of the KEAP1 tumour suppressor gene and the resulting upregulation of the NRF2 transcription factor.In this review,we detail an alternative mode of adaptation to oxidative DNA damage induced by ROS:the increased activity of the base excision repair(BER)pathway,achieved through the enhanced expression of BER enzymes and DNA repair accessory factors.These proteins,exemplified here by the CUT domain proteins CUX1,CUX2,and SATB1,stimulate the activity of BER enzymes.The ensued accelerated repair of oxidative DNA damage enables cancer cells to avoid senescence despite high ROS levels.As a by-product of this adaptation,these cancer cells exhibit increased resistance to genotoxic treatments including ionizing radiation,temozolomide,and cisplatin.Moreover,considering the intrinsic error rate associated with DNA repair and translesion synthesis,the elevated number of oxidative DNA lesions caused by high ROS leads to the accumulation of mutations in the cancer cell population,thereby contributing to tumour heterogeneity and eventually to the acquisition of resistance,a major obstacle to clinical treatment.展开更多
Alkylated DNA lesions, induced by both exogenous chemical agents and endogenous metabolites, represent a major form of DNA damage in cells. The repair of alkylation damage is critical in all cells because such damage ...Alkylated DNA lesions, induced by both exogenous chemical agents and endogenous metabolites, represent a major form of DNA damage in cells. The repair of alkylation damage is critical in all cells because such damage is cytotoxic and potentially mutagenic. Alkylation chemotherapy is a major therapeutic modality for many tumors, underscoring the importance of the repair pathways in cancer cells. Several different pathways exist for alkylation repair, including base excision and nucleotide excision repair, direct reversal by methyl-guanine methyltransferase(MGMT), and dealkylation by the AlkB homolog(ALKBH) protein family. However, maintaining a proper balance between these pathways is crucial for the favorable response of an organism to alkylating agents. Here, we summarize the progress in the field of DNA alkylation lesion repair and describe the implications for cancer chemotherapy.展开更多
DNA damage refers to the permanent alteration of nucleotide sequences during DNA replication,leading to modifications in genetic characteristics.Cells can rectify the majority of such damage through DNA damage repair(...DNA damage refers to the permanent alteration of nucleotide sequences during DNA replication,leading to modifications in genetic characteristics.Cells can rectify the majority of such damage through DNA damage repair(DDR)mechanisms-including base excision repair(BER),nucleotide excision repair(NER),mismatch repair(MMR),homologous recombination(HR),canonical non-homologous end joining(NHEJ),and alternative non-homologous end joining(alt-NHEJ)-thereby maintaining genomic stability.1 Extrachromosomal DNA(ecDNA)refers to circular DNA molecules existing outside chromosomes,which have been demonstrated to play a critical role in tumor progression and evolution.2 EcDNA has been considered a marker of genomic instability,as ecDNA-positive tumors have been found to exhibit elevated DNA replication stress and higher levels of DNA double-strand breaks(DSBs).3 However,the precise relationship between ecDNA and the DDR,as well as the specific mechanisms governing ecDNA replication and maintenance,remains to be elucidated.展开更多
Single-strand breaks （SSBs） can occur in cells either directly, or indirectly following initiation of base excision repair （BER）. SSBs generally have blocked termini lacking the conventional 5＇-phosphate and 3＇-...Single-strand breaks （SSBs） can occur in cells either directly, or indirectly following initiation of base excision repair （BER）. SSBs generally have blocked termini lacking the conventional 5＇-phosphate and 3＇-hydroxyl groups and require further processing prior to DNA synthesis and ligation. XRCC1 is devoid of any known enzymatic activity, but it can physically interact with other proteins involved in all stages of the overlapping SSB repair and BER pathways, including those that conduct the rate-limiting end-tailoring, and in many cases can stimulate their enzymatic activities. XRCC1^-/- mouse fibroblasts are most hypersensitive to agents that produce DNA lesions repaired by monofunctional glycosylase-initiated BER and that result in formation of indirect SSBs. A requirement for the deoxyribose phosphate lyase activity of DNA polymerase β （pol β） is specific to this pathway, whereas pol β is implicated in gap-filling during repair of many types of SSBs. Elevated levels of strand breaks, and diminished repair, have been demonstrated in MMS- treated XRCC1^-/-, and to a lesser extent in pol β^-/- cell lines, compared with wild-type cells. Thus a strong correlation is observed between cellular sensitivity to MMS and the ability of cells to repair MMS-induced damage. Exposure of wild-type and polβ^-/- cells to an inhibitor of PARP activity dramatically potentiates MMS-induced cytotoxicity. XRCC1^-/- cells are also sensitized by PARP inhibition demonstrating that PARP-mediated poly（ADP-ribosyl）ation plays a role in modulation of cytotoxicity beyond recruitment of XRCC 1 to sites of DNA damage.展开更多
MUTYH is a base excision repair enzyme,it plays a crucial role in the correction of DNA errors from guanine oxidation and may be considered a cell protective factor.In humans it is an adenine DNA glycosylase that remo...MUTYH is a base excision repair enzyme,it plays a crucial role in the correction of DNA errors from guanine oxidation and may be considered a cell protective factor.In humans it is an adenine DNA glycosylase that removes adenine misincorporated in 7,8-dihydro-8-oxoguanine(8-oxoG)pairs,inducing G:C to T:A transversions.MUTYH functionally cooperates with OGG1 that eliminates 8-oxodG derived from excessive reactive oxygen species production.MUTYH mutations have been linked to MUTYH associated polyposis syndrome(MAP),an autosomal recessive disorder characterized by multiple colorectal adenomas.MAP patients show a greatly increased lifetime risk for gastrointestinal cancers.The cancer risk in mono-allelic carriers associated with one MUTYH mutant allele is controversial and it remains to be clarified whether the altered functions of this protein may have a pathophysiological involvement in other diseases besides familial gastrointestinal diseases.This review evaluates the role of MUTYH,focusing on current studies of human neoplastic and non-neoplastic diseases different to colon polyposis and colorectal cancer.This will provide novel insights into the understanding of the molecular basis underlying MUTYH-related pathogenesis.Furthermore,we describe the association between MUTYH single nucleotide polymorphisms(SNPs)and different cancer and non-cancer diseases.We address the utility to increase our knowledge regarding MUTYH in the light of recent advances in the literature with the aim of a better understanding of the potential for identifying new therapeutic targets.Considering the multiple functions and interactions of MUTYH protein,its involvement in pathologies based on oxidative stress damage could be hypothesized.Although the development of extraintestinal cancer in MUTYH heterozygotes is not completely defined,the risk for malignancies of the duodenum,ovary,and bladder is also increased as well as the onset of benign and malignant endocrine tumors.The presence of MUTYH pathogenic variants is an independent predictor of poor prognosis in sporadic gastric cancer and in salivary gland secretory carcinoma,while its inhibition has been shown to reduce the survival of pancreatic ductal adenocarcinoma cells.Furthermore,some MUTYH SNPs have been associated with lung,hepatocellular and cervical cancer risk.An additional role of MUTYH seems to contribute to the prevention of numerous other disorders with an inflammatory/degenerative basis,including neurological and ocular diseases.Finally,it is interesting to note that MUTYH could be a new therapeutic target and future studies will shed light on its specific functions in the prevention of diseases and in the improvement of the chemo-sensitivity of cancer cells.展开更多
Unstable repeats are associated with various types of cancer and have been implicated in more than 40 neurode-generative disorders. Trinucleotide repeats are located in non-coding and coding regions of the genome. Stu...Unstable repeats are associated with various types of cancer and have been implicated in more than 40 neurode-generative disorders. Trinucleotide repeats are located in non-coding and coding regions of the genome. Studies of bacteria, yeast, mice and man have helped to unravel some features of the mechanism of trinucleotide expansion. Looped DNA structures comprising trinucleotide repeats are processed during replication and/or repair to generate deletions or expansions. Most in vivo data are consistent with a model in which expansion and deletion occur by different mechanisms. In mammals, microsatellite instability is complex and appears to be influenced by genetic, epigenetic and developmental factors.展开更多
Genomic deoxyribonucleic acid(DNA)is selected as the ideal carrier for preserving and transmitting the genetic information over the course of evolution.However,the genomic DNA is constantly exposed to various endogeno...Genomic deoxyribonucleic acid(DNA)is selected as the ideal carrier for preserving and transmitting the genetic information over the course of evolution.However,the genomic DNA is constantly exposed to various endogenous and environmental threats,causing a diversity of damaged bases,lesions,mismatches and base-pair modifications in the genome,eventually leading to genomic instability and cancers.Base excision repair(BER)is the most important repair mechanism,repairing a variety of DNA damages arising from oxidation,alkylation,methylation,deamination,and hydrolysis reactions.DNA glycosylases are responsible for initiating the first step of the BER pathway through cleaving the N-glycosidic bond between the damaged base and the DNA backbone.However,abnormal DNA glycosylases are associated with a variety of diseases such as cancer,cardiovascular disease,neurological disease and inflammation,suggesting the important role of DNA glycosylases in cancer diagnosis and treatment.Therefore,it is highly desirable to monitor the activity of DNA glycosylases,gaining a deep understanding of the restoration process of damaged DNA and clinical diagnosis.Recently,a series of novel DNA glycosylases detection methods with excellent performance have been developed.In this minireview,we summarize the recent advances in DNA glycosylase assays including amplification-free assay and amplification-assisted assay.Firstly,a brief introduction of amplification-free assay for DNA glycosylase is given.Then,amplification-assisted assays for DNA glycosylases are discussed in detail.Ultimately,the conclusion and prospects of the directions of DNA glycosylase assays are provided.展开更多
I completed my medical studies at the Karolinska Institute in Stockholm but have always been devoted to basic research. My longstanding interest is to understand fundamental DNA repair mechanisms in the fields of canc...I completed my medical studies at the Karolinska Institute in Stockholm but have always been devoted to basic research. My longstanding interest is to understand fundamental DNA repair mechanisms in the fields of cancer therapy, inherited human genetic disorders and ancient DNA. I initially measured DNA decay, including rates of base loss and cytosine deamination. I have dis- covered several important DNA repair proteins and determined their mechanisms of action. The discovery of uracil-DNA glycosylase defined a new category of repair enzymes with each specialized for different types of DNA damage. The base excision repair pathway was first reconstituted with human proteins in my group. Cell-free analysis for mammalian nucleotide excision repair of DNA was also developed in my laboratory. I found multiple distinct DNA ligases in mammalian cells, and led the first genetic and biochemical work on DNA ligases I, III and IV. I discovered the mam- malian exonucleases DNase III （TREX1） and IV （FEN1）. Interestingly, expression of TREXI was altered in some human autoimmune diseases. I also showed that the mutagenic DNA adduct O6-methylguanine （O6mG） is repaired without removing the guanine from DNA, identifying a sur- prising mechanism by which the methyl group is transferred to a residue in the repair protein itself. A further novel process of DNA repair discovered by my research group is the action of AlkB as an iron-dependent enzyme carrying out oxidative demethylation.展开更多
Antibody diversification is essential for an effective immune response,with somatic hypermutation(SHM)serving as a key molecular process in this adaptation.Activation-induced cytidine deaminase(AID)initiates SHM by in...Antibody diversification is essential for an effective immune response,with somatic hypermutation(SHM)serving as a key molecular process in this adaptation.Activation-induced cytidine deaminase(AID)initiates SHM by inducing DNA lesions,which are ultimately resolved into point mutations,as well as small insertions and deletions(indels).These mutational outcomes contribute to antibody affinity maturation.The mechanisms responsible for generating point mutations and indels involve the base excision repair(BER)and mismatch repair(MMR)pathways,which are well coordinated to maintain genomic integrity while allowing for beneficial mutations to occur.In this regard,translesion synthesis(TLS)polymerases contribute to the diversity of mutational outcomes in antibody genes by enabling the bypass of DNA lesions.This review summarizes our current understanding of the distinct molecular mechanisms that generate point mutations and indels during SHM.Understanding these mechanisms is critical for elucidating the development of broadly neutralizing antibodies(bnAbs)and autoantibodies,and has implications for vaccine design and therapeutics.展开更多
It has been hypothesized that DNA damage has the potential to induce DNA hypermethylation,contributing to carcinogenesis in mammals.However,there is no sufficient evidence to support that DNA damage can cause genome-w...It has been hypothesized that DNA damage has the potential to induce DNA hypermethylation,contributing to carcinogenesis in mammals.However,there is no sufficient evidence to support that DNA damage can cause genome-wide DNA hypermethylation.In this study,we demonstrated that DNA single-strand breaks with 3′blocked ends(DNA 3′blocks)not only can reinforce DNA methylation at normally methylated loci but also can induce DNA methylation at normally nonmethylated loci in plants.The CG and CHG hypermethylation tend to localize within gene bodies,with a significant proportion being de novo generated.In contrast,the CHH hypermethylation is concentrated in centromeric and pericentromeric regions,primarily being reinforced methylation.Mechanistically,DNA 3′blocks regulate the DREAM complex to induce CG and CHG methylation.Moreover,they utilize the RdDM pathway to induce CHH hypermethylation.Intriguingly,repair of DNA damage or blocking the DNA damage response can fully abolish CHH hypermethylation and partially rescue CHG hypermethylation but rarely alter CG hypermethylation,indicating that DNA damage-induced symmetric DNA methylation can serve as a form of genetic imprinting.Collectively,these results suggest that DNA damage is an important force driving the emergence and evolution of genomic DNA methylation levels and patterns in plants.展开更多
Maintaining proper DNA methylation levels in the genome requires active demethylation of DNA.However,removing the methyl group from a modified cytosine is chemically difficult and therefore,the underlying mechanism of...Maintaining proper DNA methylation levels in the genome requires active demethylation of DNA.However,removing the methyl group from a modified cytosine is chemically difficult and therefore,the underlying mechanism of demethylation had remained unclear for many years.The discovery of the first eukaryotic DNA demethylase,Arabidopsis thaliana REPRESSOR OF SILENCING 1(ROS1),led to elucidation of the 5-methylcytosine base excision repair mechanism of active DNA demethylation.In the 20 years since ROS1 was discovered,our understanding of this active DNA demethylation pathway,as well as its regulation and biological functions in plants,has greatly expanded.These exciting developments have laid the groundwork for further dissecting the regulatory mechanisms of active DNA demethylation,with potential applications in epigenome editing to facilitate crop breeding and gene therapy.展开更多
基金This study was supported by grants from the National Key Research and Development Program of China （No. 2016YFC1303804）, the National Natural Science Foundation of China （No. 81672275 and No. 81501962）, the Key Laboratory Construction Project of Science and Technology Department （No. 20170622011JC）, the Industrial Research and Development Project of Development and Reform Commission of Jilin Province （No. 2017C022）, the State Key Program of National Natural Science of China （No. 31430021）, and the Youth Fund of the First Hospital of Jilin university （No. JDYY52015003）.
文摘Background： Base excision repair （BER） plays an important role in the maintenance of genome integrity and anticancer drug resistance. This study aimed to explore the role of BER gene polymorphisms in response to chemotherapy for advanced non-small cell lung cancer （NSCLC） patients treated with platinum-based chemotherapy. Methods： During the period from November 2009 to January 2016, a total of 152 patients diagnosed with NSCLC Stage IIIB and IV in the First Hospital of Jilin University were admitted into this study. The XRCC1 G28152A, MUTYH G972C, HOGG1 C1245G. and PARPI T2444C polymorphisms of all the patients were detected by mass spectrometry. The logistic regression was used for statictical analysis. All tests were bilateral test, and a P 〈 0.05 was considered statistically significant. Results： The logistic regression model showed that the response rate of chemotherapy of the PARP1 T2444C polymorphisms, CC genotype （odds ratio [OR]： 5.216, 95% confidence interval [CI]： 1.568-17.352, P = 0.007）, TC genotype （OR： 2.692, 95% C1：1.007-7.198, P = 0.048）, as well as the genotype of TC together with CC （OR： 3.178, 95% CI： 1.229-8.219, P = 0.017） were significantly higher than those of TT wild type. There was no relationship between the MUTYH G972C, XRCC1 G28152A, and HOGGI C1245G gene polymorphisms and chemosensitivity. Conclusions： The PARPI 2444 mutation allele C might be associated with the decreased sensitivity to platinum-based chemotherapy in advanced NSCLC. These findings may be helpful in designing individualized cancer treatment.
基金supported by Canadian Institutes of Health Research(Grants MOP-326694 and MOP-391532)the National Science and Engineering Council(Grant RGPIN-2016-05155)to A.N.
文摘Cancer cells,in which the RAS and PI3K pathways are activated,produce high levels of reactive oxygen species(ROS),which cause oxidative DNA damage and ultimately cellular senescence.This process has been documented in tissue culture,mouse models,and human pre-cancerous lesions.In this context,cellular senescence functions as a tumour suppressor mechanism.Some rare cancer cells,however,manage to adapt to avoid senescence and continue to proliferate.One well-documented mode of adaptation involves increased production of antioxidants often associated with inactivation of the KEAP1 tumour suppressor gene and the resulting upregulation of the NRF2 transcription factor.In this review,we detail an alternative mode of adaptation to oxidative DNA damage induced by ROS:the increased activity of the base excision repair(BER)pathway,achieved through the enhanced expression of BER enzymes and DNA repair accessory factors.These proteins,exemplified here by the CUT domain proteins CUX1,CUX2,and SATB1,stimulate the activity of BER enzymes.The ensued accelerated repair of oxidative DNA damage enables cancer cells to avoid senescence despite high ROS levels.As a by-product of this adaptation,these cancer cells exhibit increased resistance to genotoxic treatments including ionizing radiation,temozolomide,and cisplatin.Moreover,considering the intrinsic error rate associated with DNA repair and translesion synthesis,the elevated number of oxidative DNA lesions caused by high ROS leads to the accumulation of mutations in the cancer cell population,thereby contributing to tumour heterogeneity and eventually to the acquisition of resistance,a major obstacle to clinical treatment.
文摘Alkylated DNA lesions, induced by both exogenous chemical agents and endogenous metabolites, represent a major form of DNA damage in cells. The repair of alkylation damage is critical in all cells because such damage is cytotoxic and potentially mutagenic. Alkylation chemotherapy is a major therapeutic modality for many tumors, underscoring the importance of the repair pathways in cancer cells. Several different pathways exist for alkylation repair, including base excision and nucleotide excision repair, direct reversal by methyl-guanine methyltransferase(MGMT), and dealkylation by the AlkB homolog(ALKBH) protein family. However, maintaining a proper balance between these pathways is crucial for the favorable response of an organism to alkylating agents. Here, we summarize the progress in the field of DNA alkylation lesion repair and describe the implications for cancer chemotherapy.
文摘DNA damage refers to the permanent alteration of nucleotide sequences during DNA replication,leading to modifications in genetic characteristics.Cells can rectify the majority of such damage through DNA damage repair(DDR)mechanisms-including base excision repair(BER),nucleotide excision repair(NER),mismatch repair(MMR),homologous recombination(HR),canonical non-homologous end joining(NHEJ),and alternative non-homologous end joining(alt-NHEJ)-thereby maintaining genomic stability.1 Extrachromosomal DNA(ecDNA)refers to circular DNA molecules existing outside chromosomes,which have been demonstrated to play a critical role in tumor progression and evolution.2 EcDNA has been considered a marker of genomic instability,as ecDNA-positive tumors have been found to exhibit elevated DNA replication stress and higher levels of DNA double-strand breaks(DSBs).3 However,the precise relationship between ecDNA and the DDR,as well as the specific mechanisms governing ecDNA replication and maintenance,remains to be elucidated.
文摘Single-strand breaks （SSBs） can occur in cells either directly, or indirectly following initiation of base excision repair （BER）. SSBs generally have blocked termini lacking the conventional 5＇-phosphate and 3＇-hydroxyl groups and require further processing prior to DNA synthesis and ligation. XRCC1 is devoid of any known enzymatic activity, but it can physically interact with other proteins involved in all stages of the overlapping SSB repair and BER pathways, including those that conduct the rate-limiting end-tailoring, and in many cases can stimulate their enzymatic activities. XRCC1^-/- mouse fibroblasts are most hypersensitive to agents that produce DNA lesions repaired by monofunctional glycosylase-initiated BER and that result in formation of indirect SSBs. A requirement for the deoxyribose phosphate lyase activity of DNA polymerase β （pol β） is specific to this pathway, whereas pol β is implicated in gap-filling during repair of many types of SSBs. Elevated levels of strand breaks, and diminished repair, have been demonstrated in MMS- treated XRCC1^-/-, and to a lesser extent in pol β^-/- cell lines, compared with wild-type cells. Thus a strong correlation is observed between cellular sensitivity to MMS and the ability of cells to repair MMS-induced damage. Exposure of wild-type and polβ^-/- cells to an inhibitor of PARP activity dramatically potentiates MMS-induced cytotoxicity. XRCC1^-/- cells are also sensitized by PARP inhibition demonstrating that PARP-mediated poly（ADP-ribosyl）ation plays a role in modulation of cytotoxicity beyond recruitment of XRCC 1 to sites of DNA damage.
基金the Italian Ministry of University and Research,with funds AT-Ricerca2019Curia,FFABRUNIME2019Catalano and AT-Ricerca2019Aceto.
文摘MUTYH is a base excision repair enzyme,it plays a crucial role in the correction of DNA errors from guanine oxidation and may be considered a cell protective factor.In humans it is an adenine DNA glycosylase that removes adenine misincorporated in 7,8-dihydro-8-oxoguanine(8-oxoG)pairs,inducing G:C to T:A transversions.MUTYH functionally cooperates with OGG1 that eliminates 8-oxodG derived from excessive reactive oxygen species production.MUTYH mutations have been linked to MUTYH associated polyposis syndrome(MAP),an autosomal recessive disorder characterized by multiple colorectal adenomas.MAP patients show a greatly increased lifetime risk for gastrointestinal cancers.The cancer risk in mono-allelic carriers associated with one MUTYH mutant allele is controversial and it remains to be clarified whether the altered functions of this protein may have a pathophysiological involvement in other diseases besides familial gastrointestinal diseases.This review evaluates the role of MUTYH,focusing on current studies of human neoplastic and non-neoplastic diseases different to colon polyposis and colorectal cancer.This will provide novel insights into the understanding of the molecular basis underlying MUTYH-related pathogenesis.Furthermore,we describe the association between MUTYH single nucleotide polymorphisms(SNPs)and different cancer and non-cancer diseases.We address the utility to increase our knowledge regarding MUTYH in the light of recent advances in the literature with the aim of a better understanding of the potential for identifying new therapeutic targets.Considering the multiple functions and interactions of MUTYH protein,its involvement in pathologies based on oxidative stress damage could be hypothesized.Although the development of extraintestinal cancer in MUTYH heterozygotes is not completely defined,the risk for malignancies of the duodenum,ovary,and bladder is also increased as well as the onset of benign and malignant endocrine tumors.The presence of MUTYH pathogenic variants is an independent predictor of poor prognosis in sporadic gastric cancer and in salivary gland secretory carcinoma,while its inhibition has been shown to reduce the survival of pancreatic ductal adenocarcinoma cells.Furthermore,some MUTYH SNPs have been associated with lung,hepatocellular and cervical cancer risk.An additional role of MUTYH seems to contribute to the prevention of numerous other disorders with an inflammatory/degenerative basis,including neurological and ocular diseases.Finally,it is interesting to note that MUTYH could be a new therapeutic target and future studies will shed light on its specific functions in the prevention of diseases and in the improvement of the chemo-sensitivity of cancer cells.
文摘Unstable repeats are associated with various types of cancer and have been implicated in more than 40 neurode-generative disorders. Trinucleotide repeats are located in non-coding and coding regions of the genome. Studies of bacteria, yeast, mice and man have helped to unravel some features of the mechanism of trinucleotide expansion. Looped DNA structures comprising trinucleotide repeats are processed during replication and/or repair to generate deletions or expansions. Most in vivo data are consistent with a model in which expansion and deletion occur by different mechanisms. In mammals, microsatellite instability is complex and appears to be influenced by genetic, epigenetic and developmental factors.
基金the financial support from the National Natural Science Foundation of China(No.21874060)the Fundamental Research Funds for the Central Universities(No.lzujbky-2021-it15)。
文摘Genomic deoxyribonucleic acid(DNA)is selected as the ideal carrier for preserving and transmitting the genetic information over the course of evolution.However,the genomic DNA is constantly exposed to various endogenous and environmental threats,causing a diversity of damaged bases,lesions,mismatches and base-pair modifications in the genome,eventually leading to genomic instability and cancers.Base excision repair(BER)is the most important repair mechanism,repairing a variety of DNA damages arising from oxidation,alkylation,methylation,deamination,and hydrolysis reactions.DNA glycosylases are responsible for initiating the first step of the BER pathway through cleaving the N-glycosidic bond between the damaged base and the DNA backbone.However,abnormal DNA glycosylases are associated with a variety of diseases such as cancer,cardiovascular disease,neurological disease and inflammation,suggesting the important role of DNA glycosylases in cancer diagnosis and treatment.Therefore,it is highly desirable to monitor the activity of DNA glycosylases,gaining a deep understanding of the restoration process of damaged DNA and clinical diagnosis.Recently,a series of novel DNA glycosylases detection methods with excellent performance have been developed.In this minireview,we summarize the recent advances in DNA glycosylase assays including amplification-free assay and amplification-assisted assay.Firstly,a brief introduction of amplification-free assay for DNA glycosylase is given.Then,amplification-assisted assays for DNA glycosylases are discussed in detail.Ultimately,the conclusion and prospects of the directions of DNA glycosylase assays are provided.
文摘I completed my medical studies at the Karolinska Institute in Stockholm but have always been devoted to basic research. My longstanding interest is to understand fundamental DNA repair mechanisms in the fields of cancer therapy, inherited human genetic disorders and ancient DNA. I initially measured DNA decay, including rates of base loss and cytosine deamination. I have dis- covered several important DNA repair proteins and determined their mechanisms of action. The discovery of uracil-DNA glycosylase defined a new category of repair enzymes with each specialized for different types of DNA damage. The base excision repair pathway was first reconstituted with human proteins in my group. Cell-free analysis for mammalian nucleotide excision repair of DNA was also developed in my laboratory. I found multiple distinct DNA ligases in mammalian cells, and led the first genetic and biochemical work on DNA ligases I, III and IV. I discovered the mam- malian exonucleases DNase III （TREX1） and IV （FEN1）. Interestingly, expression of TREXI was altered in some human autoimmune diseases. I also showed that the mutagenic DNA adduct O6-methylguanine （O6mG） is repaired without removing the guanine from DNA, identifying a sur- prising mechanism by which the methyl group is transferred to a residue in the repair protein itself. A further novel process of DNA repair discovered by my research group is the action of AlkB as an iron-dependent enzyme carrying out oxidative demethylation.
基金supported by the National Key Research and Development Program of China(2021YFA1301400)the National Natural Science Foundation of China(32370934)the Shanghai Jiao Tong University 2030 Initiative(2030-B23).
文摘Antibody diversification is essential for an effective immune response,with somatic hypermutation(SHM)serving as a key molecular process in this adaptation.Activation-induced cytidine deaminase(AID)initiates SHM by inducing DNA lesions,which are ultimately resolved into point mutations,as well as small insertions and deletions(indels).These mutational outcomes contribute to antibody affinity maturation.The mechanisms responsible for generating point mutations and indels involve the base excision repair(BER)and mismatch repair(MMR)pathways,which are well coordinated to maintain genomic integrity while allowing for beneficial mutations to occur.In this regard,translesion synthesis(TLS)polymerases contribute to the diversity of mutational outcomes in antibody genes by enabling the bypass of DNA lesions.This review summarizes our current understanding of the distinct molecular mechanisms that generate point mutations and indels during SHM.Understanding these mechanisms is critical for elucidating the development of broadly neutralizing antibodies(bnAbs)and autoantibodies,and has implications for vaccine design and therapeutics.
基金supported by the National Natural Science Foundation of China(grant no.32270288 to W.Q.grant no.32400245 to J.L.)+1 种基金the China Postdoctoral Science Foundation(2024M760519 to W.L.)the Beijing Life Science Academy(2024500CA0010 to W.Q.).
文摘It has been hypothesized that DNA damage has the potential to induce DNA hypermethylation,contributing to carcinogenesis in mammals.However,there is no sufficient evidence to support that DNA damage can cause genome-wide DNA hypermethylation.In this study,we demonstrated that DNA single-strand breaks with 3′blocked ends(DNA 3′blocks)not only can reinforce DNA methylation at normally methylated loci but also can induce DNA methylation at normally nonmethylated loci in plants.The CG and CHG hypermethylation tend to localize within gene bodies,with a significant proportion being de novo generated.In contrast,the CHH hypermethylation is concentrated in centromeric and pericentromeric regions,primarily being reinforced methylation.Mechanistically,DNA 3′blocks regulate the DREAM complex to induce CG and CHG methylation.Moreover,they utilize the RdDM pathway to induce CHH hypermethylation.Intriguingly,repair of DNA damage or blocking the DNA damage response can fully abolish CHH hypermethylation and partially rescue CHG hypermethylation but rarely alter CG hypermethylation,indicating that DNA damage-induced symmetric DNA methylation can serve as a form of genetic imprinting.Collectively,these results suggest that DNA damage is an important force driving the emergence and evolution of genomic DNA methylation levels and patterns in plants.
基金Excellent Young Scientist Fund of NSFC(Grant No.31922008)Strategic Priority Research Program of CAS(Grant No.XDB27040108)+1 种基金Shanghai Agriculture Applied Technology Development Program,China(Grant No.X20200101)the National Key R&D Program of China(2021YFA1300401)。
文摘Maintaining proper DNA methylation levels in the genome requires active demethylation of DNA.However,removing the methyl group from a modified cytosine is chemically difficult and therefore,the underlying mechanism of demethylation had remained unclear for many years.The discovery of the first eukaryotic DNA demethylase,Arabidopsis thaliana REPRESSOR OF SILENCING 1(ROS1),led to elucidation of the 5-methylcytosine base excision repair mechanism of active DNA demethylation.In the 20 years since ROS1 was discovered,our understanding of this active DNA demethylation pathway,as well as its regulation and biological functions in plants,has greatly expanded.These exciting developments have laid the groundwork for further dissecting the regulatory mechanisms of active DNA demethylation,with potential applications in epigenome editing to facilitate crop breeding and gene therapy.
