Rad54 and DNA Ligase IV cooperate to maintain mammalian chromatid stability
Rad54 and DNA Ligase IV cooperate to maintain mammalian chromatid stability
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DOI：
10.1101/gad.1204304
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发表时间：
2004-06-01
影响因子：
10.5
通讯作者：
Alt, FW
中科院分区：
文献类型：
--
作者：
Mills, KD;Ferguson, DO;Alt, FW
非同源末端连接（NHEJ）和同源重组（HR）代表了真核细胞中DNA双链断裂（DSB）修复的两条主要途径。 NHEJ 通过连接同源断裂末端来修复 DSB，而不管同源侧翼序列如何，而 HR 使用未损坏的同源模板来修复 DSB。尽管 NHEJ 和 HR 都明显参与了基因组稳定性的维持，但这些明显独立且机制上不同的途径如何协调仍然很大程度上尚未探索。为了研究 DSB 修复的 HR 和 NHEJ 模式之间的关系，我们生成了 NHEJ 因子 DNA 连接酶 IV (Lig4) 和 HR 因子 Rad54 双缺陷的细胞。我们证明 Lig4 和 Rad54 协同支持细胞增殖、修复自发 DSB 并防止染色体和单染色单体畸变。这些发现证明了 NHEJ 在 DNA 复制期间或之后自发发生的 DSB 修复中的作用，并揭示了 NHEJ 和 Rad54 依赖性 HR 在此类 DSB 修复中的重叠功能。
Nonhomologous end joining (NHEJ) and homologous recombination (HR) represent the two major pathways of DNA double-strand break (DSB) repair in eukaryotic cells. NHEJ repairs DSBs by ligation of cognate broken ends irrespective of homologous flanking sequences, whereas HR repairs DSBs using an undamaged homologous template. Although both NHEJ and HR have been clearly implicated in the maintenance of genome stability, how these apparently independent and mechanistically distinct pathways are coordinated remains largely unexplored. To investigate the relationship between HR and NHEJ modes of DSB repair, we generated cells doubly deficient for the NHEJ factor DNA Ligase IV (Lig4) and the HR factor Rad54. We show that Lig4 and Rad54 cooperate to support cellular proliferation, repair spontaneous DSBs, and prevent chromosome and single chromatid aberrations. These findings demonstrate a role for NHEJ in the repair of DSBs that occur spontaneously during or after DNA replication, and reveal overlapping functions for NHEJ and Rad54-dependent HR in the repair of such DSBs.