RAD52 Facilitates Mitotic DNA Synthesis Following Replication Stress
RAD52 Facilitates Mitotic DNA Synthesis Following Replication Stress
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DOI：
10.1016/j.molcel.2016.10.037
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发表时间：
2016-12-15
期刊：
影响因子：
16
通讯作者：
Hickson, Ian D.
中科院分区：
文献类型：
--
作者：
Bhowmick, Rahul;Minocherhomji, Sheroy;Hickson, Ian D.
同源重组（HR）是抵抗DNA复制应激所必需的。常见脆性位点（CFS）基因座对复制应激特别敏感，并在肿瘤中发生病理重排。在这些位点，复制应激经常激活有丝分裂中的DNA修复合成。这种有丝分裂DNA合成，称为MiDAS，需要MUS 81-EME 1内切核酸酶和Pol-delta复合物POLD 3的非催化亚基。在这里，我们研究了HR因子在促进人类细胞中的MiDAS中的贡献。我们报告说，RAD 51和BRCA 2是MiDAS的抑制剂，但需要在S期期间抵消CFS位点的复制应激。相比之下，MiDAS是RAD 52依赖性的，并且在早期有丝分裂中需要RAD 52来及时将MUS 81和POLD 3募集到CFS。我们的研究结果提供了对MiDAS的进一步机制见解，并定义了人类RAD 52的特定功能。此外，选择性抑制MiDAS可能是一种潜在的治疗策略，可以使经历复制应激的癌细胞敏感。
Homologous recombination (HR) is necessary to counteract DNA replication stress. Common fragile site (CFS) loci are particularly sensitive to replication stress and undergo pathological rearrangements in tumors. At these loci, replication stress frequently activates DNA repair synthesis in mitosis. This mitotic DNA synthesis, termed MiDAS, requires the MUS81-EME1 endonuclease and a non-catalytic subunit of the Pol-delta complex, POLD3. Here, we examine the contribution of HR factors in promoting MiDAS in human cells. We report that RAD51 and BRCA2 are dispensable for MiDAS but are required to counteract replication stress at CFS loci during S-phase. In contrast, MiDAS is RAD52 dependent, and RAD52 is required for the timely recruitment of MUS81 and POLD3 to CFSs in early mitosis. Our results provide further mechanistic insight into MiDAS and define a specific function for human RAD52. Furthermore, selective inhibition of MiDAS may comprise a potential therapeutic strategy to sensitize cancer cells undergoing replicative stress.