Cell-cycle regulation of mammalian DNA double-strand-break repair
Cell-cycle regulation of mammalian DNA double-strand-break repair
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DOI：
10.1086/514895
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发表时间：
1997-10-01
影响因子：
9.8
通讯作者：
Hendrickson, EA
中科院分区：
文献类型：
--
作者：
Hendrickson, EA
在染色体DNA中，染色体DNA的结构完整性是交联的（Friedberg等，1995）。特别是，DNA DSB似乎对存活非常重要，因此，所有活细胞都进化出修复显性细胞毒性损伤的机制，因为即使是单个未修复的DNA DSB也可能是致命事件（Frankenbergof DNA损伤）。最近，随着一系列Schwager和Frankenberg（1990）的鉴定，这种范式已经悲剧性地变得清晰起来。同样，哺乳动物免疫系统的发育也依赖于人类癌症易感综合征，这些综合征可能由DNA修复基因突变引起。因此，在一个位点特异性DNA重组过程中，称为“淋巴V（D）J重组”，它在核苷酸切除修复途径中组装了这些缺陷，导致着色性干皮病，它呈现出非连续的基因组片段（可变[V]、多样性[D]和连接[J]元件），产生免疫球蛋白，大大增加了皮肤癌的发病率（Wood 1996）。类似地，错配修复途径和T细胞受体基因的缺陷（刘易斯1994）。对V（D）J重组产物的分析已经证明，DNA方式使受影响的个体易患结肠癌和其他癌症（Kolodner 1995）。近年来，DSB是V（D）J反应机理中的重要中间体（Weaver and Alt 1997）。因此，第三种主要的DNA修复途径DNA双链断裂（DSB）修复中的缺陷变得清楚，DNA DSB是IR敏感性和V（D）J重组的整体特征。很久以前就知道其与X射线超敏反应和免疫缺陷有关，可能有趣的是，在细胞周期的不同时间起作用的多种途径，可能是乳腺癌和卵巢癌家族易感性的基础（Kinzler和Vogelstein 1997）。对细胞的增殖和倍性状态非常敏感，已经发展到确保这种DSB是这一令人兴奋的发现，再加上广泛的临床使用的辐射暴露的癌症治疗，有效地修复。最近在哺乳动物和酵母模型系统中的工作表明，至少有两个dishas引起了对DNA DSB修复的突然和强烈的兴趣。本文将重点关注由多达四种离散复合物介导的促进DSB修复的证据（Petrini等人证明DNA DSB修复有几种不同的机制，它们在1997年发挥作用; Kanaar和Hoeijmakers 1997）。在一个途径中，非同源重组修复，DNA在细胞周期的不同阶段。几年前就已经知道，在哺乳动物中，修复不需要或很少需要重新连接的链末端的同源性。DNA DSB修复中的两个离散复合物缺陷表现为两种表型，电离辐射（IR）超敏反应，并涉及该途径，DNA依赖性蛋白激酶（DNA-PK）复合物和RAD 50共同免疫缺陷。这两个看似无关的生物学过程，实际上是由需求丛联系在一起的，主要作用于细胞周期的G1/早期S期。在同源重组修复中，DNA外端的双链断裂是反应的中间产物.因此，哺乳动物细胞暴露于IR诱导损伤，例如在具有DSB的区域和模板（通常是姐妹染色单体链切断、单链断裂、DSB和碱基或同源染色体）之间需要高度同源性，从所述模板指导修复。这种类型的修复是由RAD 52复合体执行的，它...
The structural integrity of chromosomal DNA is of crosslinks (Friedberg et al. 1995), in chromosomal DNA. In particular, DNA DSBs appear to be the preparamount importance to survival, and, consequently, all living cells have evolved mechanisms for the repair dominant cytotoxic lesions, since even a single unrepaired DNA DSB can be a lethal event (Frankenbergof DNA lesions. This paradigm recently has been made tragically clear, with the identification of a series Schwager and Frankenberg 1990). Similarly, the development of the mammalian immune system is dependent of human cancer-predisposition syndromes that can arise from mutations in DNA-repair genes. Thus, de- on a site-specific DNA-recombination process, called ‘‘lymphoid V (D) J recombination,’’that assembles the fects in the nucleotide-excision repair pathway result in xeroderma pigmentosum, which presents with a noncontiguousgenomicsegments (variable [V], diversity [D], and joining [J] elements) to create immunoglobulin greatly increased incidence of skin cancer (Wood 1996). Similarly, defects in the mismatch repair path- and T-cell receptor genes (Lewis 1994). Analyses of V (D) J recombination products have proven that DNA way predispose affected individuals to colon cancer and to other cancers (Kolodner 1995). Recently, it has DSBs are an essential intermediate in the V (D) J-reaction mechanism (Weaver and Alt 1997). Thus, the repair of become clear that defects in a third major DNA-repair pathway, DNA double-strand-break (DSB) repair, DNA DSBs is an integral feature of IR sensitivity and of V (D) J recombination. which have long been known to be associated with xray hypersensitivity and immune deficiency, probably Intriguingly, a variety of pathways that act at different times during the cell cycle and that are likely to underlie the familial predisposition to breast cancer and to ovarian cancer (Kinzler and Vogelstein 1997). be very sensitive to the proliferative and ploidy states of the cell have evolved to ensure that such DSBs are This exciting revelation, coupled with the widespread clinical use of radiation exposure for cancer therapy, repaired effectively. Recent work in mammalian and in yeast model systems suggests that at least two dishas prompted a sudden and intense interest in DNA DSB repair. This review will focus on the evidence tinct pathways, mediated by as many as four discrete complexes, facilitate the repair of DSBs (Petrini et al. that demonstrates that there are several different mechanisms of DNA DSB repair, which operate dur- 1997; Kanaar and Hoeijmakers 1997). In one pathway, nonhomologous recombinational repair, DNA ing distinct phases of the cell cycle. It has been known for several years that, in mammals, repair requires no or very little homology on the ends of the strands being rejoined. Two discrete complexes defects in DNA DSB repair manifest themselves in two phenotypes, ionizing-radiation (IR) hypersensitivity and implicated in this pathway, the DNA-dependent protein kinase (DNA-PK) complex and the RAD50 comimmune deficiencies. These two seemingly unrelated biological processes, in fact, are linked by the requirement plex, act primarily during the G1/early S phase of the cell cycle. In homologous recombinational repair, exof DNA DSBs as reaction intermediates. Thus, the exposure of mammalian cells to IR induces lesions, such as tensive homology is required between the region with the DSB and a template (usually a sister chromatid strand scissions, single-stranded breaks, DSBs, and base or a homologous chromosome) from which repair is directed. This type of repair is performed either by the RAD52 complex, which …