Structural Maintenance of Chromosomes Flexible Hinge Domain Containing 1 (SMCHD1) Promotes Non-homologous End Joining and Inhibits Homologous Recombination Repair upon DNA Damage
Structural Maintenance of Chromosomes Flexible Hinge Domain Containing 1 (SMCHD1) Promotes Non-homologous End Joining and Inhibits Homologous Recombination Repair upon DNA Damage
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染色体柔性铰链结构域 1 (SMCHD1) 的结构维护促进非同源末端连接并抑制 DNA 损伤时的同源重组修复
DOI：
10.1074/jbc.m114.601179
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发表时间：
2014-12-05
影响因子：
4.8
通讯作者：
Zhou Songyang
中科院分区：
文献类型：
--
作者：
Tang, Mengfan;Li, Yujing;Zhou Songyang
背景：SMCHD1在DNA损伤反应中的作用在很大程度上是未知的。结果：SMCHD1向DNA损伤灶的募集受53BP1调控。敲除SMCHD1会损害细胞存活，并降低非同源末端连接（NHEJ）的效率，同时提高同源重组（HR）的效率。结论：SMCHD1同时调节NHEJ和HR。意义：我们的发现将进一步理解细胞如何采取不同的修复途径。染色体结构维持柔性铰链结构域1（SMCHD1）已被证明参与基因沉默和DNA损伤。然而，SMCHD1如何参与DNA损伤的确切机制在很大程度上仍然未知。在这里，我们提出的证据表明，SMCHD1招聘到DNA损伤灶是由53BP1。敲除SMCHD1导致DNA损伤后异常的H2AX灶积聚和受损的细胞存活，证明了SMCHD1在DNA损伤修复中的关键作用。DNA损伤诱导后，SMCHD1缺失导致53BP1病灶减少和BRCA1病灶增加，以及非同源末端连接（NHEJ）效率降低和同源重组（HR）水平升高。总之，这些结果表明SMCHD1在促进NHEJ和抑制HR修复中响应DNA损伤的重要功能。
Background: The role of SMCHD1 in DNA damage response is largely unknown. Results: SMCHD1 recruitment to DNA damage foci is regulated by 53BP1. Knocking out SMCHD1 compromised cell survival, and decreased the efficiency of non-homologous end joining (NHEJ) while elevating the efficiency of homologous recombination (HR). Conclusion: SMCHD1 regulates both NHEJ and HR. Significance: Our findings should further understanding of how cells adopt different repair pathways.Structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) has been shown to be involved in gene silencing and DNA damage. However, the exact mechanisms of how SMCHD1 participates in DNA damage remains largely unknown. Here we present evidence that SMCHD1 recruitment to DNA damage foci is regulated by 53BP1. Knocking out SMCHD1 led to aberrant H2AX foci accumulation and compromised cell survival upon DNA damage, demonstrating the critical role of SMCHD1 in DNA damage repair. Following DNA damage induction, SMCHD1 depletion resulted in reduced 53BP1 foci and increased BRCA1 foci, as well as less efficient non-homologous end joining (NHEJ) and elevated levels of homologous recombination (HR). Taken together, these results suggest an important function of SMCHD1 in promoting NHEJ and repressing HR repair in response to DNA damage.