Meiotic prophase I is a long and complex phase. Homologous recombination is an important process that occurs between homologous chromosomes during meiotic prophase I. Formation of chiasmata, which hold homologous chro...Meiotic prophase I is a long and complex phase. Homologous recombination is an important process that occurs between homologous chromosomes during meiotic prophase I. Formation of chiasmata, which hold homologous chromosomes together until the metaphase I to anaphase I transition, is critical for proper chromosome segregation. Recent studies have suggested that the SPO 11 proteins have conserved functions in a number of organisms in generating sites of double-stranded DNA breaks （DSBs） that are thought to be the starting points of homologous recombination. Processing of these sites of DSBs requires the function of RecA homologs, such as RAD5 1, DMC 1, and others, as suggested by mutant studies; thus the failure to repair these meiotic DSBs results in abnormal chromosomal alternations, leading to disrupted meiosis. Recent discoveries on the functions of these RecA homologs have improved the understanding of the mechanisms underlying meiotic homologous recombination.展开更多
In microcantilever-based label-free biodetection technologies, deflection changes induced by adsorptions of double-stranded DNA （dsDNA） molecules on Au-layer surface are greatly affected by the mechanical, thermal a...In microcantilever-based label-free biodetection technologies, deflection changes induced by adsorptions of double-stranded DNA （dsDNA） molecules on Au-layer surface are greatly affected by the mechanical, thermal and electrical properties of DNA biofilm. In this paper, the elastic properties of dsDNA biofilm are studied. First, the Parsegian＇s empirical potential based on a mesoscopic liq- uid crystal theory is employed to describe the interaction energy among coarse-grained DNA cylinders. Then, con- sidering a Gaussian distribution of DNA interaxial distance, the thought experiment method is used to derive an analyti- cal expression for Young＇s modulus of DNA biofilm with a stochastic packing pattern for the first time. Results show that Young＇s modulus of DNA biofilm is on the order of 10 MPa. These findings could provide a simple and effective method to evaluate the mechanical properties of soft biofilm on snbstrate.展开更多
The adsorption dynamics of double-stranded DNA(dsDNA)molecules on a graphene oxide(GO)surface are important for applications of DNA/GO functional structures in biosensors,biomedicine and materials science.In this work...The adsorption dynamics of double-stranded DNA(dsDNA)molecules on a graphene oxide(GO)surface are important for applications of DNA/GO functional structures in biosensors,biomedicine and materials science.In this work,molecular dynamics simulations were used to examine the adsorption of different length dsDNA molecules(from 4 bp to24 bp)on the GO surface.The dsDNA molecules could be adsorbed on the GO surface through the terminal bases and stand on the GO surface.For short dsDNA(4 bp)molecules,the double-helix structure was partially or totally broken and the adsorption dynamics was affected by the structural fluctuation of short dsDNA and the distribution of the oxidized groups on the GO surface.For long dsDNA molecules(from 8 bp to 24 bp)adsorption is stable.By nonlinear fitting of the contact angle between the axis of the dsDNA molecule and the GO surface,we found that a dsDNA molecule adsorbed on a GO surface has the chance of orienting parallel to the GO surface if the length of the dsDNA molecule is longer than 54 bp.We attributed this behavior to the flexibility of dsDNA molecules.With increasing length,the flexibility of dsDNA molecules also increases,and this increasing flexibility gives an adsorbed dsDNA molecule more chance of reaching the GO surface with the free terminal.This work provides a whole picture of adsorption of dsDNA molecules on the GO surface and should be of benefit for the design of DNA/GO based biosensors.展开更多
The double-stranded DNA (dsDNA) probe contains two different protein binding sites. One is for DNA- binding proteins to be detected and the other is for a DNA restriction enzyme. The two sites were arranged together w...The double-stranded DNA (dsDNA) probe contains two different protein binding sites. One is for DNA- binding proteins to be detected and the other is for a DNA restriction enzyme. The two sites were arranged together with no base interval. The working principle of the capturing dsDNA probe is described as follows: the capturing probe can be cut with the DNA restriction enzyme (such as EcoR I) to cause a sticky terminal, if the probe is not bound with a target protein, and the sticky terminal can be extended and labeled with Cy3-dUTP by DNA polymerase. When the probe is bound with a target protein, the probe is not capable to be cut by the restriction enzyme because of space obstruction. The amount of the target DNA binding proteins can be measured according to the variations of fluorescent signals of the corresponding probes.展开更多
We investigate the statistical mechanics properties of a nonlinear dynamics model of the denaturation of the DNA double-helix and study the effects of salt concentration and temperature on denaturation transition of D...We investigate the statistical mechanics properties of a nonlinear dynamics model of the denaturation of the DNA double-helix and study the effects of salt concentration and temperature on denaturation transition of DNA. The specific heat, entropy, and denaturation temperature of the system versus salt concentration are obtained. These results show that the denaturation of DNA not only depends on the temperature but also is influenced by the salt concentration in the solution of DNA, which are in agreement with experimental measurement.展开更多
Polymerase-tautomeric model for untargeted delayed base substitution mutations is proposed.Structural analysis of bases insertion showed that any canonical bases may be inserted opposite rare tautomeric forms of thymi...Polymerase-tautomeric model for untargeted delayed base substitution mutations is proposed.Structural analysis of bases insertion showed that any canonical bases may be inserted opposite rare tautomeric forms of thymine T3*,adenines A2*and A4*so that between them hydrogen bonds are formed.Canonical adenine and cytosine can be incorporated opposite canonical thymine only.Canonical thymine and guanine can be incorporated opposite canonical adenine only.If in the synthesis of DNA containing rare tautomeric forms of thymine T3*,adenines A2*and A4*,involved DNA polymerases with relatively high fidelity of synthesis,mutations not appear.However,if further DNA synthesis will involve DNA polymerases having a low fidelity of synthesis,there may be base substitution mutations.It was shown that the conclusion made in the Tomasetti and Vogelstein cancer risk model that the formation of about 67%of all mutations was not caused by exposure to any mutagens is erroneous.展开更多
5-Hydroxymethylcytosine(5hmC)is a crucial DNA modification that participates in the regulation of various physiological processes.Although several methods have been developed to map 5hmC,there is still a high demand f...5-Hydroxymethylcytosine(5hmC)is a crucial DNA modification that participates in the regulation of various physiological processes.Although several methods have been developed to map 5hmC,there is still a high demand for genome-wide mapping at single-base resolution.Consequently,we developed a double-stranded DNA deamination sequencing(DDD-seq)approach for genome-wide mapping of 5hmC at single-base resolution.DDD-seq utilizes the double-stranded DNA deaminase SsdA_(cat)from Pseudomonas syringae,which efficiently deaminates cytosine(C),5-methylcytosine(5mC),5hmC,5-formylcytosine(5fC),and 5-carboxylcytosine(5caC)in duplex DNA,but not glycosylated 5hmC(5gmC).In DDD-seq,C,5mC,5fC,and 5caC in dsDNA are deaminated by SsdA_(cat)and read as T in sequencing,while 5gmC resists deamination,allowing its identification by detecting as C in sequencing.The map of 5hmC generated by DDD-seq inmouse cerebellum tissue closely aligns with that obtained from the ACE-seq method.Applying DDD-seq to mouse cerebellum tissue subjected to chronic sleep deprivation revealed significant changes of 5hmC distribution in genomic DNA.In contrast to previous single-stranded deaminase APOBEC3A-based mapping methods that require denaturation of dsDNA into ssDNA,DDD-seq eliminates this step,reducing risks associated with incomplete denaturation and simplifying sequencing library construction.Additionally,SsdA_(cat)demonstrates superior thermostability and activity across a wide range of pH values and temperatures,making DDD-seq applicable in broader scenarios with more accessible conditions.Collectively,the DDD-seq method is straightforward,bisulfite-free,and eliminates the need for DNA denaturation step,making it a valuable tool for mapping 5hmC in genomes at single-base resolution.展开更多
The interaction of double-stranded （ds） and G-quadruplex （G4） DNA with sulfonyl 5-fluorouracil derivatives （5-fluoro-l-（arylsulfonyl） pyrimidine-2,4 （1H,3H）-diones） was investigated in this research, in whic...The interaction of double-stranded （ds） and G-quadruplex （G4） DNA with sulfonyl 5-fluorouracil derivatives （5-fluoro-l-（arylsulfonyl） pyrimidine-2,4 （1H,3H）-diones） was investigated in this research, in which Au electrodes modified with ds-DNA or G4-DNAs were used as a working electrode. The investigation showed that the binding affinity with G4-DNA was significantly increased when 5-fluorouracil （5-FU） was modified with arylsulfonyl groups. The presence of strong electron-withdrawing groups on benzene sulfonyl 5-FU greatly enhanced the binding selectivity （kG4-DNA/kds-DNA）. Such results provided new insights into the potential connections between the chemical structure of drug candidates and their anticancer activities.展开更多
Background Deoxyribonuclease 2(DNaseⅡ)plays a key role in clearing cytoplasmic double-stranded DNA(dsDNA).Deficiency of DNaseⅡleads to DNA accumulation in the cytoplasm.Persistent dsDNA in neurons is an early pathol...Background Deoxyribonuclease 2(DNaseⅡ)plays a key role in clearing cytoplasmic double-stranded DNA(dsDNA).Deficiency of DNaseⅡleads to DNA accumulation in the cytoplasm.Persistent dsDNA in neurons is an early pathological hallmark of senescence and neurodegenerative diseases including Alzheimer’s disease(AD).However,it is not clear how DNaseⅡand neuronal cytoplasmic dsDNA influence neuropathogenesis.Tau hyperphosphorylation is a key factor for the pathogenesis of AD.The effect of DNaseⅡand neuronal cytoplasmic dsDNA on neuronal tau hyperphosphorylation remains unclarified.Methods The levels of neuronal DNaseⅡand dsDNA in WT and Tau-P301S mice of different ages were measured by immunohistochemistry and immunolabeling,and the levels of DNaseⅡin the plasma of AD patients were measured by ELISA.To investigate the impact of DNaseⅡon tauopathy,the levels of phosphorylated tau,phosphokinase,phosphatase,synaptic proteins,gliosis and proinflammatory cytokines in the brains of neuronal DNaseⅡ-deficient WT mice,neuronal DNaseⅡ-deficient Tau-P301S mice and neuronal DNaseⅡ-overexpressing Tau-P301S mice were evaluated by immunolabeling,immunoblotting or ELISA.Cognitive performance was determined using the Morris water maze test,Y-maze test,novel object recognition test and open field test.Results The levels of DNaseⅡwere significantly decreased in the brains and the plasma of AD patients.DNaseⅡalso decreased age-dependently in the neurons of WT and Tau-P301S mice,along with increased dsDNA accumulation in the cytoplasm.The DNA accumulation induced by neuronal DNaseⅡdeficiency drove tau phosphorylation by upregulating cyclin-dependent-like kinase-5(CDK5)and calcium/calmodulin activated protein kinaseⅡ(CaMKⅡ)and downregulating phosphatase protein phosphatase 2A(PP2A).Moreover,DNaseⅡknockdown induced and significantly exacerbated neuron loss,neuroinflammation and cognitive deficits in WT and Tau-P301S mice,respectively,while overexpression of neuronal DNaseⅡexhibited therapeutic benefits.Conclusions DNaseⅡdeficiency and cytoplasmic dsDNA accumulation can initiate tau phosphorylation,suggesting DNaseⅡas a potential therapeutic target for tau-associated disorders.展开更多
目的运用meta分析方法系统评价补肾方剂治疗男性不育症患者精子DNA损伤(SDF)的有效性和安全性。方法从中国知网、维普、万方、PubMed、Cochrane Library、Embase、Web of Science数据库中检索补肾方剂改善SDF的随机对照试验(RCT)研究,...目的运用meta分析方法系统评价补肾方剂治疗男性不育症患者精子DNA损伤(SDF)的有效性和安全性。方法从中国知网、维普、万方、PubMed、Cochrane Library、Embase、Web of Science数据库中检索补肾方剂改善SDF的随机对照试验(RCT)研究,对文献进行方法学质量评价,运用RevMan5.3.5软件进行meta分析,并对结局指标进行GRADE质量分级。结果共纳入17项RCT研究,涉及2164例男性患者。与西医常规治疗相比,补肾方剂能够显著改善男性不育症患者DNA碎片指数(DFI)(MD=-6.50,95%CI:-7.88~-5.11,P<0.01),提高配偶妊娠率(RR=2.11,95%CI:1.12~4.00,P=0.87)、精子总活率(MD=5.56,95%CI:4.39~6.74,P<0.01)、前向运动精子百分率(MD=6.82,95%CI:5.62~8.03,P<0.01)、精子浓度(MD=6.51,95%CI:3.81~9.21,P<0.01)和正常形态精子百分率(MD=1.26,95%CI:0.45~2.06,P<0.01),且补肾方剂不会增加不良反应的发生。结论低到中等质量证据表明,与西医常规治疗相比,补肾方剂在改善男性不育症患者DFI、精液参数、配偶妊娠率等方面具有一定优势,且安全性较好。展开更多
DNA double-stranded break(DSB)is one of the most catastrophic damages of genotoxic insult.Inappropriate repair of DNA DSBs results in the loss of genetic information,mutation,and the generation of harmful genomic rear...DNA double-stranded break(DSB)is one of the most catastrophic damages of genotoxic insult.Inappropriate repair of DNA DSBs results in the loss of genetic information,mutation,and the generation of harmful genomic rearrangements,which predisposes an organism to immunodeficiency,neurological damage,and cancer.The tumor repressor p53 plays a key role in DNA damage response,and has been found to be mutated in 50%of human cancer.p53,p63,and p73 are three members of the p53 gene family.Recent discoveries have shown that human p53 gene encodes at least 12 isoforms.Different p53 members and isoforms play various roles in orchestrating DNA damage response to maintain genomic integrity.This review briefly explores the functions of p53 and its isoforms in DNA DSB repair.展开更多
In our previous study, complete single DNA strands which were obtained from nuclei, chloroplasts and plant mitochondria obeyed Chargaff’s second parity rule, although those which were obtained from animal mitochondri...In our previous study, complete single DNA strands which were obtained from nuclei, chloroplasts and plant mitochondria obeyed Chargaff’s second parity rule, although those which were obtained from animal mitochondria deviated from the rule. On the other hand, plant mitochondria obeyed another different rule after their classification. Complete single DNA strand sequences obtained from chloroplasts, plant mitochondria, and animal mitochondria, were divided into the coding and non-coding regions. The non-coding region, which was the complementary coding region on the reverse strand, was incorporated as a coding region in the forward strand. When the nucleotide contents of the coding region or non-coding regions were plotted against the composition of the four nucleotides in the complete single DNA strand, it was determined that chloroplast and plant mitochondrial DNA obeyed Chargaff’s second parity rule in both the coding and non-coding regions. However, animal mitochondrial DNA deviated from this rule. In chloroplast and plant mitochondrial DNA, which obey Chargaff’s second parity rule, the lines of regression for G (purine) and C (pyrimidine) intersected with regression lines for A (purine) and T (pyrimidines), respectively, at around 0.250 in all cases. On the other hand, in animal mitochondrial DNA, which deviates from Chargaff’s second parity rule, only regression lines due to the content of homonucleotides or their analogs in the coding or non-coding region against those in the complete single DNA strand intersected at around 0.250 at the horizontal axis. Conversely, the intersection of the two lines of regression (G and A or C and T) against the contents of heteronucleotides or their analogs shifted from 0.25 in both coding and non-coding regions. Nucleotide alternations in chloroplasts and plant mitochondria are strictly regulated, not only by the proportion of homonucleotides and their analogs, but also by the heteronucleotides and their analogs. They are strictly regulated in animal mitochondria only by the content of homonucleotides and their analogs.展开更多
基金The authors thank Alexandra Surcel and Carey L Hendrix Lord for helpful comments on this manuscript.The work in our laboratory is supported by grants from the National Science Foundation(IBN-0077832,MCB-9896340,MCB-0092075)the National Institutes of Health(R0 1 GM63871)+3 种基金the US Department of Agriculture(2001-35301-10570 and 2003-35301-13313)Wuxing L was partially supported by the Intercollege Graduate Degree Program in Plant PhysiologyHong M gratefully acknowledges the support of the John Simon Guggenheim Foundationthe National Institutes of Health(F33 GM72245-1).
文摘Meiotic prophase I is a long and complex phase. Homologous recombination is an important process that occurs between homologous chromosomes during meiotic prophase I. Formation of chiasmata, which hold homologous chromosomes together until the metaphase I to anaphase I transition, is critical for proper chromosome segregation. Recent studies have suggested that the SPO 11 proteins have conserved functions in a number of organisms in generating sites of double-stranded DNA breaks （DSBs） that are thought to be the starting points of homologous recombination. Processing of these sites of DSBs requires the function of RecA homologs, such as RAD5 1, DMC 1, and others, as suggested by mutant studies; thus the failure to repair these meiotic DSBs results in abnormal chromosomal alternations, leading to disrupted meiosis. Recent discoveries on the functions of these RecA homologs have improved the understanding of the mechanisms underlying meiotic homologous recombination.
基金supported by the National Natural Science Foundation of China(11272193 and 10872121)the Shanghai Leading Academic Discipline Project(S30106)
文摘In microcantilever-based label-free biodetection technologies, deflection changes induced by adsorptions of double-stranded DNA （dsDNA） molecules on Au-layer surface are greatly affected by the mechanical, thermal and electrical properties of DNA biofilm. In this paper, the elastic properties of dsDNA biofilm are studied. First, the Parsegian＇s empirical potential based on a mesoscopic liq- uid crystal theory is employed to describe the interaction energy among coarse-grained DNA cylinders. Then, con- sidering a Gaussian distribution of DNA interaxial distance, the thought experiment method is used to derive an analyti- cal expression for Young＇s modulus of DNA biofilm with a stochastic packing pattern for the first time. Results show that Young＇s modulus of DNA biofilm is on the order of 10 MPa. These findings could provide a simple and effective method to evaluate the mechanical properties of soft biofilm on snbstrate.
基金Project supported by the National Natural Science Foundation of China (Grant No.11974366)the Fundamental Research Funds for the Central Universities+2 种基金Chinathe Supercomputer Center of the Chinese Academy of Sciencesthe Shanghai Supercomputer Center of China。
文摘The adsorption dynamics of double-stranded DNA(dsDNA)molecules on a graphene oxide(GO)surface are important for applications of DNA/GO functional structures in biosensors,biomedicine and materials science.In this work,molecular dynamics simulations were used to examine the adsorption of different length dsDNA molecules(from 4 bp to24 bp)on the GO surface.The dsDNA molecules could be adsorbed on the GO surface through the terminal bases and stand on the GO surface.For short dsDNA(4 bp)molecules,the double-helix structure was partially or totally broken and the adsorption dynamics was affected by the structural fluctuation of short dsDNA and the distribution of the oxidized groups on the GO surface.For long dsDNA molecules(from 8 bp to 24 bp)adsorption is stable.By nonlinear fitting of the contact angle between the axis of the dsDNA molecule and the GO surface,we found that a dsDNA molecule adsorbed on a GO surface has the chance of orienting parallel to the GO surface if the length of the dsDNA molecule is longer than 54 bp.We attributed this behavior to the flexibility of dsDNA molecules.With increasing length,the flexibility of dsDNA molecules also increases,and this increasing flexibility gives an adsorbed dsDNA molecule more chance of reaching the GO surface with the free terminal.This work provides a whole picture of adsorption of dsDNA molecules on the GO surface and should be of benefit for the design of DNA/GO based biosensors.
文摘The double-stranded DNA (dsDNA) probe contains two different protein binding sites. One is for DNA- binding proteins to be detected and the other is for a DNA restriction enzyme. The two sites were arranged together with no base interval. The working principle of the capturing dsDNA probe is described as follows: the capturing probe can be cut with the DNA restriction enzyme (such as EcoR I) to cause a sticky terminal, if the probe is not bound with a target protein, and the sticky terminal can be extended and labeled with Cy3-dUTP by DNA polymerase. When the probe is bound with a target protein, the probe is not capable to be cut by the restriction enzyme because of space obstruction. The amount of the target DNA binding proteins can be measured according to the variations of fluorescent signals of the corresponding probes.
基金The project supported by the Doctoral Foundation of the Ministry of Education of China under Grant No.20010614005
文摘We investigate the statistical mechanics properties of a nonlinear dynamics model of the denaturation of the DNA double-helix and study the effects of salt concentration and temperature on denaturation transition of DNA. The specific heat, entropy, and denaturation temperature of the system versus salt concentration are obtained. These results show that the denaturation of DNA not only depends on the temperature but also is influenced by the salt concentration in the solution of DNA, which are in agreement with experimental measurement.
文摘Polymerase-tautomeric model for untargeted delayed base substitution mutations is proposed.Structural analysis of bases insertion showed that any canonical bases may be inserted opposite rare tautomeric forms of thymine T3*,adenines A2*and A4*so that between them hydrogen bonds are formed.Canonical adenine and cytosine can be incorporated opposite canonical thymine only.Canonical thymine and guanine can be incorporated opposite canonical adenine only.If in the synthesis of DNA containing rare tautomeric forms of thymine T3*,adenines A2*and A4*,involved DNA polymerases with relatively high fidelity of synthesis,mutations not appear.However,if further DNA synthesis will involve DNA polymerases having a low fidelity of synthesis,there may be base substitution mutations.It was shown that the conclusion made in the Tomasetti and Vogelstein cancer risk model that the formation of about 67%of all mutations was not caused by exposure to any mutagens is erroneous.
基金supported by the National Key R&D Program of China(grant nos.2022YFC3400700 and 2022YFA0806600)the Fundamental Research Funds for the Central Universities(grant no.2042024kf0022)+1 种基金the National Natural Science Foundation of China(grant nos.22074110,22277093,and 22307099)the Key Research and Development Project of Hubei Province(grant no.2023BCB094).
文摘5-Hydroxymethylcytosine(5hmC)is a crucial DNA modification that participates in the regulation of various physiological processes.Although several methods have been developed to map 5hmC,there is still a high demand for genome-wide mapping at single-base resolution.Consequently,we developed a double-stranded DNA deamination sequencing(DDD-seq)approach for genome-wide mapping of 5hmC at single-base resolution.DDD-seq utilizes the double-stranded DNA deaminase SsdA_(cat)from Pseudomonas syringae,which efficiently deaminates cytosine(C),5-methylcytosine(5mC),5hmC,5-formylcytosine(5fC),and 5-carboxylcytosine(5caC)in duplex DNA,but not glycosylated 5hmC(5gmC).In DDD-seq,C,5mC,5fC,and 5caC in dsDNA are deaminated by SsdA_(cat)and read as T in sequencing,while 5gmC resists deamination,allowing its identification by detecting as C in sequencing.The map of 5hmC generated by DDD-seq inmouse cerebellum tissue closely aligns with that obtained from the ACE-seq method.Applying DDD-seq to mouse cerebellum tissue subjected to chronic sleep deprivation revealed significant changes of 5hmC distribution in genomic DNA.In contrast to previous single-stranded deaminase APOBEC3A-based mapping methods that require denaturation of dsDNA into ssDNA,DDD-seq eliminates this step,reducing risks associated with incomplete denaturation and simplifying sequencing library construction.Additionally,SsdA_(cat)demonstrates superior thermostability and activity across a wide range of pH values and temperatures,making DDD-seq applicable in broader scenarios with more accessible conditions.Collectively,the DDD-seq method is straightforward,bisulfite-free,and eliminates the need for DNA denaturation step,making it a valuable tool for mapping 5hmC in genomes at single-base resolution.
基金supported by the National Natural Science Foundation of China (21073133,20843007)Zhejiang Provincial Natural Science Foundation of China (Y4080177,Y4090248,Y5100283)Zhejiang Provincial Ministry of Education (Y200907715)
文摘The interaction of double-stranded （ds） and G-quadruplex （G4） DNA with sulfonyl 5-fluorouracil derivatives （5-fluoro-l-（arylsulfonyl） pyrimidine-2,4 （1H,3H）-diones） was investigated in this research, in which Au electrodes modified with ds-DNA or G4-DNAs were used as a working electrode. The investigation showed that the binding affinity with G4-DNA was significantly increased when 5-fluorouracil （5-FU） was modified with arylsulfonyl groups. The presence of strong electron-withdrawing groups on benzene sulfonyl 5-FU greatly enhanced the binding selectivity （kG4-DNA/kds-DNA）. Such results provided new insights into the potential connections between the chemical structure of drug candidates and their anticancer activities.
基金supported by funding from the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB39050600)the National Natural Science Foundation of China(82150107 and 81971073)the National Key Research and Development Program of China(2020YFA0712402).
文摘Background Deoxyribonuclease 2(DNaseⅡ)plays a key role in clearing cytoplasmic double-stranded DNA(dsDNA).Deficiency of DNaseⅡleads to DNA accumulation in the cytoplasm.Persistent dsDNA in neurons is an early pathological hallmark of senescence and neurodegenerative diseases including Alzheimer’s disease(AD).However,it is not clear how DNaseⅡand neuronal cytoplasmic dsDNA influence neuropathogenesis.Tau hyperphosphorylation is a key factor for the pathogenesis of AD.The effect of DNaseⅡand neuronal cytoplasmic dsDNA on neuronal tau hyperphosphorylation remains unclarified.Methods The levels of neuronal DNaseⅡand dsDNA in WT and Tau-P301S mice of different ages were measured by immunohistochemistry and immunolabeling,and the levels of DNaseⅡin the plasma of AD patients were measured by ELISA.To investigate the impact of DNaseⅡon tauopathy,the levels of phosphorylated tau,phosphokinase,phosphatase,synaptic proteins,gliosis and proinflammatory cytokines in the brains of neuronal DNaseⅡ-deficient WT mice,neuronal DNaseⅡ-deficient Tau-P301S mice and neuronal DNaseⅡ-overexpressing Tau-P301S mice were evaluated by immunolabeling,immunoblotting or ELISA.Cognitive performance was determined using the Morris water maze test,Y-maze test,novel object recognition test and open field test.Results The levels of DNaseⅡwere significantly decreased in the brains and the plasma of AD patients.DNaseⅡalso decreased age-dependently in the neurons of WT and Tau-P301S mice,along with increased dsDNA accumulation in the cytoplasm.The DNA accumulation induced by neuronal DNaseⅡdeficiency drove tau phosphorylation by upregulating cyclin-dependent-like kinase-5(CDK5)and calcium/calmodulin activated protein kinaseⅡ(CaMKⅡ)and downregulating phosphatase protein phosphatase 2A(PP2A).Moreover,DNaseⅡknockdown induced and significantly exacerbated neuron loss,neuroinflammation and cognitive deficits in WT and Tau-P301S mice,respectively,while overexpression of neuronal DNaseⅡexhibited therapeutic benefits.Conclusions DNaseⅡdeficiency and cytoplasmic dsDNA accumulation can initiate tau phosphorylation,suggesting DNaseⅡas a potential therapeutic target for tau-associated disorders.
文摘目的运用meta分析方法系统评价补肾方剂治疗男性不育症患者精子DNA损伤(SDF)的有效性和安全性。方法从中国知网、维普、万方、PubMed、Cochrane Library、Embase、Web of Science数据库中检索补肾方剂改善SDF的随机对照试验(RCT)研究,对文献进行方法学质量评价,运用RevMan5.3.5软件进行meta分析,并对结局指标进行GRADE质量分级。结果共纳入17项RCT研究,涉及2164例男性患者。与西医常规治疗相比,补肾方剂能够显著改善男性不育症患者DNA碎片指数(DFI)(MD=-6.50,95%CI:-7.88~-5.11,P<0.01),提高配偶妊娠率(RR=2.11,95%CI:1.12~4.00,P=0.87)、精子总活率(MD=5.56,95%CI:4.39~6.74,P<0.01)、前向运动精子百分率(MD=6.82,95%CI:5.62~8.03,P<0.01)、精子浓度(MD=6.51,95%CI:3.81~9.21,P<0.01)和正常形态精子百分率(MD=1.26,95%CI:0.45~2.06,P<0.01),且补肾方剂不会增加不良反应的发生。结论低到中等质量证据表明,与西医常规治疗相比,补肾方剂在改善男性不育症患者DFI、精液参数、配偶妊娠率等方面具有一定优势,且安全性较好。
基金supported by the National Natural Science Foundation of China(Nos.31571511 and 31871500)
文摘DNA double-stranded break(DSB)is one of the most catastrophic damages of genotoxic insult.Inappropriate repair of DNA DSBs results in the loss of genetic information,mutation,and the generation of harmful genomic rearrangements,which predisposes an organism to immunodeficiency,neurological damage,and cancer.The tumor repressor p53 plays a key role in DNA damage response,and has been found to be mutated in 50%of human cancer.p53,p63,and p73 are three members of the p53 gene family.Recent discoveries have shown that human p53 gene encodes at least 12 isoforms.Different p53 members and isoforms play various roles in orchestrating DNA damage response to maintain genomic integrity.This review briefly explores the functions of p53 and its isoforms in DNA DSB repair.
文摘In our previous study, complete single DNA strands which were obtained from nuclei, chloroplasts and plant mitochondria obeyed Chargaff’s second parity rule, although those which were obtained from animal mitochondria deviated from the rule. On the other hand, plant mitochondria obeyed another different rule after their classification. Complete single DNA strand sequences obtained from chloroplasts, plant mitochondria, and animal mitochondria, were divided into the coding and non-coding regions. The non-coding region, which was the complementary coding region on the reverse strand, was incorporated as a coding region in the forward strand. When the nucleotide contents of the coding region or non-coding regions were plotted against the composition of the four nucleotides in the complete single DNA strand, it was determined that chloroplast and plant mitochondrial DNA obeyed Chargaff’s second parity rule in both the coding and non-coding regions. However, animal mitochondrial DNA deviated from this rule. In chloroplast and plant mitochondrial DNA, which obey Chargaff’s second parity rule, the lines of regression for G (purine) and C (pyrimidine) intersected with regression lines for A (purine) and T (pyrimidines), respectively, at around 0.250 in all cases. On the other hand, in animal mitochondrial DNA, which deviates from Chargaff’s second parity rule, only regression lines due to the content of homonucleotides or their analogs in the coding or non-coding region against those in the complete single DNA strand intersected at around 0.250 at the horizontal axis. Conversely, the intersection of the two lines of regression (G and A or C and T) against the contents of heteronucleotides or their analogs shifted from 0.25 in both coding and non-coding regions. Nucleotide alternations in chloroplasts and plant mitochondria are strictly regulated, not only by the proportion of homonucleotides and their analogs, but also by the heteronucleotides and their analogs. They are strictly regulated in animal mitochondria only by the content of homonucleotides and their analogs.
