SETDB1, HP1 and SUV39 promote repositioning of 53BP1 to extend resection during homologous recombination in G2 cells.
SETDB1, HP1 and SUV39 promote repositioning of 53BP1 to extend resection during homologous recombination in G2 cells.
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DOI：
10.1093/nar/gkv722
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发表时间：
2015-09-18
影响因子：
14.9
通讯作者：
Jeggo P
中科院分区：
文献类型：
--
作者：
Alagoz M;Katsuki Y;Ogiwara H;Ogi T;Shibata A;Kakarougkas A;Jeggo P
最近的研究表明，同源重组（HR）需要染色质抑制以及在DNA双链断裂（DSB）的松弛。HP 1和SUV 39 H1/2是HR必需的抑制因子，在此，我们将SETDB 1鉴定为促进HR的额外压缩因子。抑制因子，如BRCA 1，是启动切除，但促进扩展步骤，导致减少RPA或RAD 51灶和HR照射G2细胞。压缩因子的消耗不抑制BRCA 1募集，但在IR后8小时，BRCA 1病灶较小，与对照细胞相比位置异常。BRCA 1促进53 BP 1重新定位到扩大的病灶的外围，并形成一个缺乏的核心，BRCA 1变得扩大并定位在53 BP 1内部。压缩因子的耗尽排除了辐射诱导病灶处的这些变化。因此，抑制因子是BRCA 1在促进HR过程中53 BP 1重新定位的功能所必需的。此外，在未受损细胞中这些抑制因子的耗尽会导致着丝粒序列处的姐妹染色单体缔合减少。我们提出了一个模型，这些发现可能是功能性的联系。
Recent studies have shown that homologous recombination (HR) requires chromatin repression as well as relaxation at DNA double strand breaks (DSBs). HP1 and SUV39H1/2 are repressive factors essential for HR. Here, we identify SETDB1 as an additional compacting factor promoting HR. Depletion of HP1, SUV39, SETDB1 or BRCA1 confer identical phenotypes. The repressive factors, like BRCA1, are dispensable for the initiation of resection but promote the extension step causing diminished RPA or RAD51 foci and HR in irradiated G2 cells. Depletion of the compacting factors does not inhibit BRCA1 recruitment but at 8 h post IR, BRCA1 foci are smaller and aberrantly positioned compared to control cells. BRCA1 promotes 53BP1 repositioning to the periphery of enlarged foci and formation of a devoid core with BRCA1 becoming enlarged and localized internally to 53BP1. Depletion of the compacting factors precludes these changes at irradiation-induced foci. Thus, the repressive factors are required for BRCA1 function in promoting the repositioning of 53BP1 during HR. Additionally, depletion of these repressive factors in undamaged cells causes diminished sister chromatid association at centromeric sequences. We propose a model for how these findings may be functionally linked.