Genomic instability is an underlying hallmark of cancer and is closely associated with defects in DNA damage repair (DDR). Chromatin relaxation is a prerequisite for DDR, but how chromatin accessibility is regulated remains elusive. Here we report that the histone deacetylase SIRT6 coordinates with the chromatin remodeler CHD4 to promote chromatin relaxation in response to DNA damage. Upon DNA damage, SIRT6 rapidly translocates to DNA damage sites, where it interacts with and recruits CHD4. Once at the damage sites, CHD4 displaces heterochromatin protein 1 (HP1) from histone H3 lysine 9 trimethylation (H3K9me3). Notably, loss of SIRT6 or CHD4 leads to impaired chromatin relaxation and disrupted DNA repair protein recruitment. These molecular changes, in-turn, lead to defective homologous recombination (HR) and cancer cell hypersensitivity to DNA damaging agents. Furthermore, we show that SIRT6-mediated CHD4 recruitment has a specific role in DDR within compacted chromatin by HR in G2 phase, which is an ataxia telangiectasia mutated (ATM)-dependent process. Taken together, our results identify a novel function for SIRT6 in recruiting CHD4 onto DNA double-strand breaks. This newly identified novel molecular mechanism involves CHD4-dependent chromatin relaxation and competitive release of HP1 from H3K9me3 within the damaged chromatin, which are both essential for accurate HR.

中文翻译：

---

SIRT6与CHD4协同作用以促进染色质松弛和DNA修复。

基因组不稳定性是癌症的基本特征，并且与DNA损伤修复（DDR）的缺陷密切相关。染色质松弛是DDR的先决条件，但是如何控制染色质的可及性仍然不清楚。在这里我们报告说，组蛋白脱乙酰基酶SIRT6与染色质重塑剂CHD4协同作用，以促进响应DNA损伤的染色质松弛。受到DNA损伤后，SIRT6迅速转移到DNA损伤位点，与CHD4相互作用并募集CHD4。一旦到达损伤部位，CHD4就会从组蛋白H3赖氨酸9三甲基化（H3K9me3）中置换异染色质蛋白1（HP1）。值得注意的是，SIRT6或CHD4的缺失会导致染色质松弛减弱和DNA修复蛋白募集受损。这些分子的变化反过来 导致缺陷的同源重组（HR）和癌细胞对DNA破坏剂的超敏性。此外，我们表明，SIRT6介导的CHD4募集在致密染色质中由DDR在G2相中的DDR中具有特定作用，这是共济失调性毛细血管扩张突变（ATM）依赖性过程。综上所述，我们的结果确定了SIRT6在将CHD4募集到DNA双链断裂上的新功能。这个新发现的新颖分子机制涉及CHD4依赖的染色质松弛和在受损的染色质中从H3K9me3竞争性释放HP1，这对于精确的HR都是必不可少的。我们的结果确定了SIRT6在将CHD4募集到DNA双链断裂上的新功能。这个新发现的新颖分子机制涉及CHD4依赖的染色质松弛和在受损的染色质中从H3K9me3竞争性释放HP1，这对于精确的HR都是必不可少的。我们的结果确定了SIRT6在将CHD4募集到DNA双链断裂上的新功能。这个新发现的新颖分子机制涉及CHD4依赖的染色质松弛和在受损的染色质中从H3K9me3竞争性释放HP1，这对于精确的HR都是必不可少的。