Ku70 Corrupts DNA Repair in the Absence of the Fanconi Anemia Pathway
Ku70 Corrupts DNA Repair in the Absence of the Fanconi Anemia Pathway
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DOI：
10.1126/science.1192277
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发表时间：
2010-07-09
期刊：
影响因子：
56.9
通讯作者：
Patel, Ketan J.
中科院分区：
文献类型：
--
作者：
Pace, Paul;Mosedale, Georgina;Patel, Ketan J.
一个保守的DNA修复反应是有缺陷的人类遗传疾病范可尼贫血（FA）。一些FA基因的突变损害同源重组和易错DNA修复，使FA细胞对DNA交联剂敏感。我们发现FA基因FANCC和非同源末端连接（NHEJ）因子Ku70之间存在遗传相互作用。FANCC和Ku70的破坏抑制了对交联剂的敏感性，减少了染色体断裂，并逆转了有缺陷的同源重组。Ku70直接与游离DNA末端结合，使其参与NHEJ修复。我们表明，纯化的FANCD 2，FA通路的下游效应，可能会拮抗Ku70活性通过修改这样的DNA基板。这些结果揭示了FA途径在加工DNA末端中的功能，从而将双链断裂修复从失败的NHEJ转向同源重组。
A conserved DNA repair response is defective in the human genetic illness Fanconi anemia (FA). Mutation of some FA genes impairs homologous recombination and error-prone DNA repair, rendering FA cells sensitive to DNA cross-linking agents. We found a genetic interaction between the FA gene FANCC and the nonhomologous end joining (NHEJ) factor Ku70. Disruption of both FANCC and Ku70 suppresses sensitivity to cross-linking agents, diminishes chromosome breaks, and reverses defective homologous recombination. Ku70 binds directly to free DNA ends, committing them to NHEJ repair. We show that purified FANCD2, a downstream effector of the FA pathway, might antagonize Ku70 activity by modifying such DNA substrates. These results reveal a function for the FA pathway in processing DNA ends, thereby diverting double-strand break repair away from abortive NHEJ and toward homologous recombination.