Université de Paris and Université Paris-Saclay, INSERM, iRCM/IBFJ CEA, UMR Stabilité Génétique Cellules Souches et Radiations, Fontenay-aux-Roses, France.
Régulation spatiale des génomes, Institut Pasteur, CNRS UMR3525, Paris, France.
EMBO J. 2022 Jan 4;41(1):e108813. doi: 10.15252/embj.2021108813. Epub 2021 Nov 24.
Heterochromatin is a conserved feature of eukaryotic chromosomes, with central roles in gene expression regulation and maintenance of genome stability. How heterochromatin proteins regulate DNA repair remains poorly described. In the yeast Saccharomyces cerevisiae, the silent information regulator (SIR) complex assembles heterochromatin-like chromatin at sub-telomeric chromosomal regions. SIR-mediated repressive chromatin limits DNA double-strand break (DSB) resection, thus protecting damaged chromosome ends during homologous recombination (HR). As resection initiation represents the crossroads between repair by non-homologous end joining (NHEJ) or HR, we asked whether SIR-mediated heterochromatin regulates NHEJ. We show that SIRs promote NHEJ through two pathways, one depending on repressive chromatin assembly, and the other relying on Sir3 in a manner that is independent of its heterochromatin-promoting function. Via physical interaction with the Sae2 protein, Sir3 impairs Sae2-dependent functions of the MRX (Mre11-Rad50-Xrs2) complex, thereby limiting Mre11-mediated resection, delaying MRX removal from DSB ends, and promoting NHEJ.
异染色质是真核染色体的保守特征，在基因表达调控和基因组稳定性维持中起着核心作用。异染色质蛋白如何调节 DNA 修复仍知之甚少。在酵母酿酒酵母中，沉默信息调节（SIR）复合物在端粒附近的染色体区域组装类似异染色质的染色质。SIR 介导的抑制性染色质限制 DNA 双链断裂（DSB）的切除，从而在同源重组（HR）期间保护受损的染色体末端。由于切口起始代表非同源末端连接（NHEJ）或 HR 修复的交叉路口，我们询问 SIR 介导的异染色质是否调节 NHEJ。我们表明，SIR 通过两种途径促进 NHEJ，一种途径依赖于抑制性染色质的组装，另一种途径依赖于 Sir3，而不依赖于其促进异染色质的功能。通过与 Sae2 蛋白的物理相互作用，Sir3 损害了 MRX（Mre11-Rad50-Xrs2 复合物）复合物中 Sae2 依赖性功能，从而限制了 Mre11 介导的切除，延迟了 MRX 从 DSB 末端的去除，并促进了 NHEJ。
