辐射作用下含修复DNA主链断裂随机动力学理论的研究——单链与双链断裂规律

按照我们在文献[1]中给出的辐射诱发含修复DNA主链断裂随机动力学理论数学模型,在此基础上,本文进一步导出了两种不同形成过程的双链断裂变化规律。在一定近似下,可以对SSB及DSB的实验结果作出满意的解释。我们的理论可以避免靶学说与击中理论的主要缺点,在一定条件下则又可以还原为靶理论结果,而且本理论还具有容纳更多因素的优点。     

耐辐射异常球菌DNA损伤修复重要功能蛋白的研究进展

耐辐射异常球菌(DR)具有对致死剂量的电离辐射极端的抗性,但对其超强辐射抗性的分子机制仍缺乏深入了解。耐辐射异常球菌基因组分析显示其拥有许多与修复相关的基因或蛋白,转录组学和蛋白组学分析等研究表明该菌能通过复杂的代谢途径控制的网络系统有效地调整并修复DNA。近年来已分析和鉴定了许多与DNA损伤修复,特别是辐射诱导的DNA双链断裂修复相关的蛋白,这些功能蛋白的研究有助于我们加深对其极端抗性机理的认识。主要针对DR双链断裂修复系统中重要功能蛋白的研究进展进行了概述,以期为DNA修复机理的基础研究及应用研究奠定基础。     

植物DNA双链断裂损伤修复机制研究进展

DNA双链断裂(DSBs)是细胞最严重的损伤形式之一。高等动植物中主要通过非同源末端连接（NHEJ）途径进行DNA双链断裂修复。该途径不依赖DNA同源性,由一些修复因子如：Ku蛋白异二聚体、DNA-PKcs 、XRCC4、ligaseⅣ等,将断裂末端直接连接进行修复。综述了植物DNA双链断裂损伤修复的主要途径及其相关基因研究的进展,探讨了植物DNA损伤修复研究中存在的问题与发展方向。     

ADP核糖基化对DNA损伤修复的调控

DNA链断裂在细胞中持续发生,可导致染色体重排和基因组不稳定或细胞死亡。最常见的是DNA单链断裂,单个细胞每天可成千上万次发生,会阻碍RNA/DNA聚合酶的反应,干扰基因转录和基因组复制。如果DNA单链断裂没有得到及时修复,在基因组复制过程中会演变转变为DNA双链断裂,从而激活一系列的DNA损伤反应。在DNA的损伤修复途径中,ADP核糖基化行使了非常重要的功能,本文将详细阐述ADP核糖基化参与的具体DNA损伤修复途径。     

UV-B与植物DNA: 损伤与修复

臭氧衰减导致地表紫外辐射增强,而紫外线辐射对植物表皮细胞的DNA具有损害作用,可导致环丁烷嘧啶二聚体和6,4-光产物的形成.植物DNA对UV-B辐射的响应具有一定的敏感性,这种敏感性与不同的UV-B辐射剂量和不同植物细胞的原生质体有关,表现出一定的剂量-效应关系.植物可以通过多种途径来修复紫外诱导的DNA损伤,主要包括光修复、碱基切除修复、核苷酸切除修复和重组修复等.DNA的修复能力与紫外辐射的剂量在一定程度上呈正相关.概述了对紫外辐射引起的DNA损伤、植物DNA对UV-B辐射响应的敏感性、损伤的修复和未来的研究方向.     

德国研究小组发现与DNA双链断裂修复相关新基因

<正>德国研究人员在寻找参与修复脱氧核糖核酸(DNA)双链断裂的基因方面获得进展。研究小组在人类细胞中找到61个位点,并发现了此前未知的与DNA双链断裂修复有关的基因。该研究结果将显著加速DNA修复基因的继续搜寻,并带来新的医疗应用可能。相关研究成果发表在6月29日的《公共科学图书馆.生物学》杂志上。     

耐辐射球菌DNA修复机制研究新进展

耐辐射球菌是迄今为止发现的最耐辐射的原核生物,是研究DNA损伤与修复的模式生物.根据国内外实验室和本实验在耐辐射球菌研究上取得的最新研究成果,本文从该细菌的结构特征、分子防御机制、重要修复基因、基因组学和蛋白质组学等方面综述了耐辐射球菌在DNA修复机制方面取得的进展,探讨了未来揭示该细菌独特高效的DNA修复分子机理可能采取的途径.     

小分子化合物靶向DNA连接酶Ⅳ提高CRISPR/Cas9基因编辑效率的研究进展

基因编辑工具能够在DNA链上制造特定位点双链断裂(Double-strand breaks,DSB)。细胞内具有修复DSB的2种不同途径,即同源重组(HDR)和非同源末端连接(NHEJ)。NHEJ与HDR之间相互竞争,互为替代DNA修复途径。DNA连接酶IV参与NHEJ途径并发挥重要作用。DNA连接酶IV抑制剂可以抑制DNA修复通路中NHEJ的效率,同时可以提高HDR的效率。为了优选小分子化合物实现更有效的基因定点插入,综述了SCR7、NU7026、白藜芦醇、L755507这4种不同的小分子化合物在CRISPR/Cas9基因编辑效率上的研究,归纳了这4种小分子化合物在其中发挥的作用,并用生物信息学软件模拟所用小分子化合物与DNA连接酶IV的对接。在此基础上,对这4种小分子化合物提高基因编辑效率的研究前景进行了展望。     

茶多酚对机体清除自由基和抗DNA损伤的作用

通过茶多酚(TP)对青、老年NIH小鼠血清中丙二醛(MDA)、红细胞超氧化物歧化酶(SOD)和过氧化氢酶(CAT)活性的作用研究了它对机体自由基的清除功效,并以人体淋巴细胞DNA单链断裂为指标研究了TP对辐射诱发的DNA损伤的保护作用.结果显示:0.05％TP饮饲15天可明显降低青、老年小鼠血清MDA含量(P<0.01)、提高青、老年小鼠红细胞SOD活性(P<0.05)和老年小鼠CAT活性(P<0.05),但青年鼠CAT活性未见提高.0.1～1.0mg/mL TP处理,可明显降低20 GY ~(50)Coγ-线诱发的人体外周淋巴细胞DNA单链断裂,其中以0.1mg/mL TP处理24小时为最佳.     

植物DNA错配修复系统响应Cd胁迫的研究进展

Cd胁迫下植物细胞内会出现不同形式的DNA损伤(如碱基错配、DNA单/双链断裂和甲基化),DNA损伤会迅速诱导DNA损伤响应(DDR)信号,如ATM、ATR及其下游的信号通路包括细胞周期阻滞、细胞内复制、细胞凋亡以及不同形式的DNA修复途径(如同源重组修复HR、DNA错配修复MMR)。植物细胞DNA MMR系统中的异源二聚体MutSα(MSH2/MSH6)、MutSβ(MSH2/MSH3)、MutSg(MSH2/MSH7)、MutLα(MLH1/PMS1)与有关酶如增殖细胞核抗原(PCNA)、DNA复制因子C(RFC)、DNA核酸外切酶1(EXO1)、单链结合蛋白(RPA)、核酸内切酶FEN1、DNA聚合酶delta(d)和DNA连接酶相互作用,启动DNA MMR反应,从而在感知Cd诱导的DNA损伤、修复DNA损伤、激活细胞周期检验点、确保基因组DNA的稳定性和DNA复制的精确性等方面发挥关键作用。然而,MutS缺失的植物细胞会绕过DNA MMR系统参与的细胞周期阻滞,从而严重影响植物的耐Cd性能。本文重点介绍了植物DNA MMR系统对Cd胁迫的响应以及表观遗传对DNA MMR系统的调控作用机理。     

Direct coupling between meiotic DNA replication and recombination initiation

During meiosis in Saccharomyces cerevisiae, DNA replication occurs 1. 5 to 2 hours before recombination initiates by DNA double-strand break formation. We show that replication and recombination initiation are directly linked. Blocking meiotic replication prevented double-strand break formation in a replication-checkpoint-independent manner, and delaying replication of a chromosome segment specifically delayed break formation in that segment. Consequently, the time between replication and break formation was held constant in all regions. We suggest that double-strand break formation occurs as part of a process initiated by DNA replication, which thus determines when meiotic recombination initiates on a regional rather than a cell-wide basis.     

Drosophila BLM in double-strand break repair by synthesis-dependent strand annealing

Bloom syndrome, characterized by a predisposition to cancer, is caused by mutation of the RecQ DNA helicase gene BLM. The precise function of BLM remains unclear. Previous research suggested that Drosophila BLM functions in the repair of DNA double-strand breaks. Most double-strand breaks in flies are repaired by homologous recombination through the synthesis-dependent strand-annealing pathway. Here, we demonstrate that Drosophila BLM mutants are severely impaired in their ability to carry out repair DNA synthesis during synthesis-dependent strand annealing. Consequently, repair in the mutants is completed by error-prone pathways that create large deletions. These results suggest a model in which BLM maintains genomic stability by promoting efficient repair DNA synthesis and thereby prevents double-strand break repair by less precise pathways.     

DNA gyrase and the supercoiling of DNA

Negative supercoiling of bacterial DNA by DNA gyrase influences all metabolic processes involving DNA and is essential for replication. Gyrase supercoils DNA by a mechanism called sign inversion, whereby a positive supercoil is directly inverted to a negative one by passing a DNA segment through a transient double-strand break. Reversal of this scheme relaxes DNA, and this mechanism also accounts for the ability of gyrase to catenate and uncatenate DNA rings. Each round of supercoiling is driven by a conformational change induced by adenosine triphosphate (ATP) binding: ATP hydrolysis permits fresh cycles. The inhibition of gyrase by two classes of antimicrobials reflects its composition from two reversibly associated subunits. The A subunit is particularly associated with the concerted breakage-and-rejoining of DNA and the B subunit mediates energy transduction. Gyrase is a prototype for a growing class of prokaryotic and eukaryotic topoisomerases that interconvert complex forms by way of transient double-strand breaks.     

ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex

The ataxia-telangiectasia mutated (ATM) kinase signals the presence of DNA double-strand breaks in mammalian cells by phosphorylating proteins that initiate cell-cycle arrest, apoptosis, and DNA repair. We show that the Mre11-Rad50-Nbs1 (MRN) complex acts as a double-strand break sensor for ATM and recruits ATM to broken DNA molecules. Inactive ATM dimers were activated in vitro with DNA in the presence of MRN, leading to phosphorylation of the downstream cellular targets p53 and Chk2. ATM autophosphorylation was not required for monomerization of ATM by MRN. The unwinding of DNA ends by MRN was essential for ATM stimulation, which is consistent with the central role of single-stranded DNA as an evolutionarily conserved signal for DNA damage.     

A sense of the end

How a cell distinguishes a double-strand break from the end of a chromosome has long fascinated cell biologists. It was thought that the protection of chromosomal ends required either a telomere-specific complex or the looping back of the 3' TG-rich overhang to anneal with a homologous double-stranded repeat. These models must now accommodate the findings that complexes involved in nonhomologous end joining play important roles in normal telomere length maintenance, and that subtelomeric chromatin changes in response to the DNA damage checkpoint. A hypothetical chromatin assembly checkpoint may help to explain why telomeres and the double-strand break repair machinery share essential components.     

Chromosome segregation errors as a cause of DNA damage and structural chromosome aberrations

Various types of chromosomal aberrations, including numerical (aneuploidy) and structural (e.g., translocations, deletions), are commonly found in human tumors and are linked to tumorigenesis. Aneuploidy is a direct consequence of chromosome segregation errors in mitosis, whereas structural aberrations are caused by improperly repaired DNA breaks. Here, we demonstrate that chromosome segregation errors can also result in structural chromosome aberrations. Chromosomes that missegregate are frequently damaged during cytokinesis, triggering a DNA double-strand break response in the respective daughter cells involving ATM, Chk2, and p53. We show that these double-strand breaks can lead to unbalanced translocations in the daughter cells. Our data show that segregation errors can cause translocations and provide insights into the role of whole-chromosome instability in tumorigenesis.     

Postreplicative formation of cohesion is required for repair and induced by a single DNA break

Sister-chromatid cohesion, established during replication by the protein complex cohesin, is essential for both chromosome segregation and double-strand break (DSB) repair. Normally, cohesion formation is strictly limited to the S phase of the cell cycle, but DSBs can trigger cohesion also after DNA replication has been completed. The function of this damage-induced cohesion remains unknown. In this investigation, we show that damage-induced cohesion is essential for repair in postreplicative cells in yeast. Furthermore, it is established genome-wide after induction of a single DSB, and it is controlled by the DNA damage response and cohesin-regulating factors. We thus define a cohesion establishment pathway that is independent of DNA duplication and acts together with cohesion formed during replication in sister chromatid-based DSB repair.