The interplay between nonhomologous end-joining and cell cycle checkpoint factors in development, genomic stability, and tumorigenesis
The interplay between nonhomologous end-joining and cell cycle checkpoint factors in development, genomic stability, and tumorigenesis
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DOI：
10.1101/sqb.2000.65.395
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发表时间：
2000-01-01
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影响因子：
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通讯作者：
Alt, FW
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作者：
Ferguson, DO;Sekiguchi, JM;Alt, FW
《冷泉港定量生物学研讨会》，卷LXV，© 2000冷泉港实验室出版社0-87969-605-2/00。395个基因片段。虽然发夹编码基因片段的末端连接需要所有五种已知的NHEJ因子，但DNA-PKcs对于钝RSS末端的连接相对较难，这表明它可能对连接前的末端加工更重要（Gao等，1998 a）。已经产生了NHEJ途径的每种组分缺陷的小鼠，并显示出共同的表型，例如受损的V（D）J重组，以及令人惊讶的差异（Sekiguchi et al.1999）。携带三种DNA-PK成分中任何一种突变的小鼠都是可以存活的，并且以预期的孟德尔比率出生，但Ku缺乏与DNA-PKcs缺乏相反，会导致培养细胞生长发育不良和过早衰老。令人惊讶的是，Lig 4或XRCC 4缺陷导致晚期胚胎死亡（到E17天），与整个中枢神经系统（CNS）的中间区中的大量细胞凋亡相关，中间区是由经历分化的有丝分裂后神经元占据的层（Frank等，1998; Gao等，1998 b）。在经历复杂分化程序的细胞中末端连接缺陷的背景下，广泛的细胞死亡提供了淋巴细胞和神经元发育之间的平行关系，并恢复了VDJ样过程可能支配神经元发育的推测。此外，最近显示Ku缺陷而非DNA-PKcs缺陷赋予与Lig 4/XRCC 4缺陷类似但比Lig 4/XRCC 4缺陷更轻的神经元凋亡表型（Gu等，2000）。这一发现提供了强有力的支持，神经元凋亡表型的NHEJ缺陷的结果，因为它是由四个进化上保守的组件的任何损失产生。由于Ku缺陷小鼠尚未报道有神经行为异常，中枢神经系统的凋亡表型的影响仍然是一个谜。所有NHEJ缺陷小鼠或胚胎均表现出严重的联合免疫缺陷（SCID）表型，这是由缺陷性V（D）J重组和淋巴细胞发育受阻引起的。然而，阻塞的严重程度各不相同。DNA-PKcs缺陷在以后的生活中允许显著的泄漏，而Ku蛋白的缺陷允许不太明显的泄漏，Lig 4或XRCC 4缺陷似乎赋予更完全的阻断。总之，各种末端连接缺陷的表型已经产生了NHEJ途径的模型，其描述了DNA-PKcs的相对可分配性，在大多数事件中需要Ku 70/80，并且在所有事件中绝对需要Lig 4/XRCC 4（Sekiguchi等人，1999）。
Cold Spring Harbor Symposia on Quantitative Biology, Volume LXV.© 2000 Cold Spring Harbor Laboratory Press 0-87969-605-2/00. 395 ticipating gene segments. Although end-joining of the hairpin-coding gene segments requires all five known NHEJ factors, DNA-PKcs is relatively dispensable for joining of the blunt RSS ends, suggesting that it may be more important for end-processing prior to ligation (Gao et al. 1998a).Mice deficient in each of the components of the NHEJ pathway have been generated and reveal common phenotypes, such as impaired V (D) J recombination, as well as surprising differences (Sekiguchi et al. 1999). Mice harboring mutation of any one of the three DNA-PK components are viable and born in expected Mendelian ratios, but Ku deficiency, as opposed to DNA-PKcs deficiency, confers stunted growth and premature senescence of cultured cells. Surprisingly, Lig4 or XRCC4 deficiency causes late embryonic lethality (by day E17), associated with massive apoptosis in the intermediate zone throughout the central nervous system (CNS), a layer populated by postmitotic neurons undergoing differentiation (Frank et al. 1998; Gao et al. 1998b). Widespread cell death in the context of end-joining deficiency in cells undergoing a complex differentiation program provided a parallel between lymphocyte and neuronal development and revived speculation that a VDJ-like process may govern neuronal development. In addition, it was recently shown that Ku deficiency, but not DNA-PKcs deficiency, confers a neuronal apoptosis phenotype similar to, but milder than, Lig4/XRCC4 deficiency (Gu et al. 2000). This finding provides strong support that the neuronal apoptosis phenotype results from an NHEJ deficiency, since it is generated by loss of any of the four evolutionarily conserved components. Since Ku-deficient mice have not been reported to have a neurobehavioral abnormality, the implications of the apoptotic CNS phenotype remain a mystery. All NHEJ-deficient mice or embryos display a severe combined immunodeficiency (SCID) phenotype resulting from defective V (D) J recombination and blocked lymphocyte development. The severity of the block, however, varies. DNA-PKcs deficiency allows significant leakiness later in life, whereas deficiency of either Ku protein allows a less prominent leakiness, and Lig4 or XRCC4 deficiency appears to confer a more complete block. Taken together, the phenotypes of the various endjoining deficiencies have yielded a model for the NHEJ pathway that depicts a relative dispensability for the DNA-PKcs, requirement of Ku70/80 in most events, and an absolute requirement for Lig4/XRCC4 in all events (Sekiguchi et al. 1999).