Department of Biology, Technion-Israel Institute of Technology, Haifa, Israel.
J Mol Cell Biol. 2018 Aug 1;10(4):341-357. doi: 10.1093/jmcb/mjx050.
Cells have evolved DNA damage response (DDR) to repair DNA lesions and thus preserving genomic stability and impeding carcinogenesis. DNA damage induction is accompanied by transient transcription repression. Here, we describe a previously unrecognized role of chromodomain Y-like (CDYL1) protein in fortifying double-strand break (DSB)-induced transcription repression and repair. We showed that CDYL1 is rapidly recruited to damaged euchromatic regions in a poly (ADP-ribose) polymerase 1 (PARP1)-dependent, but ataxia telangiectasia mutated (ATM)-independent, manner. While the C-terminal region, containing the enoyl-CoA hydratase like (ECH) domain, of CDYL1 binds to poly (ADP-ribose) (PAR) moieties and mediates CDYL1 accumulation at DNA damage sites, the chromodomain and histone H3 trimethylated on lysine 9 (H3K9me3) mark are dispensable for its recruitment. Furthermore, CDYL1 promotes the recruitment of enhancer of zeste homolog 2 (EZH2), stimulates local increase of the repressive methyl mark H3K27me3, and promotes transcription silencing at DSB sites. In addition, following DNA damage induction, CDYL1 depletion causes persistent G2/M arrest and alters H2AX and replication protein A (RPA2) phosphorylation. Remarkably, the 'traffic-light reporter' system revealed that CDYL1 mainly promotes homology-directed repair (HDR) of DSBs in vivo. Consequently, CDYL1-knockout cells display synthetic lethality with the chemotherapeutic agent, cisplatin. Altogether, our findings identify CDYL1 as a new component of the DDR and suggest that the HDR-defective 'BRCAness' phenotype of CDYL1-deficient cells could be exploited for eradicating cancer cells harboring CDYL1 mutations.
细胞已经进化出 DNA 损伤反应 (DDR) 来修复 DNA 损伤，从而保持基因组稳定性并阻碍致癌作用。DNA 损伤的诱导伴随着转录的瞬时抑制。在这里，我们描述了一个以前未被识别的 chromodomain Y-like (CDYL1) 蛋白在强化双链断裂 (DSB) 诱导的转录抑制和修复中的作用。我们表明，CDYL1 以多聚 ADP-核糖聚合酶 1 (PARP1) 依赖但 ATM 不依赖的方式迅速被招募到受损的常染色质区域。虽然 CDYL1 的 C 端区域包含烯酰基辅酶 A 水解酶样 (ECH) 结构域，与聚 ADP-核糖 (PAR) 部分结合，并介导 CDYL1 在 DNA 损伤部位的积累，但 chromodomain 和组蛋白 H3 赖氨酸 9 上的三甲基化 (H3K9me3) 标记对于其募集是可有可无的。此外，CDYL1 促进增强子结合锌指蛋白 2 (EZH2) 的募集，刺激局部增加抑制性甲基标记 H3K27me3，并促进 DSB 部位的转录沉默。此外，在 DNA 损伤诱导后，CDYL1 耗尽会导致持续的 G2/M 期阻滞，并改变 H2AX 和复制蛋白 A (RPA2) 的磷酸化。值得注意的是，“交通信号灯报告系统”显示，CDYL1 主要在体内促进 DSB 的同源定向修复 (HDR)。因此，CDYL1 敲除细胞与化疗药物顺铂表现出合成致死性。总之，我们的发现确定了 CDYL1 是 DDR 的一个新组成部分，并表明 CDYL1 缺陷细胞的 HDR 缺陷“BRCAness”表型可以被利用来根除携带 CDYL1 突变的癌细胞。
