Consequently, CDYL1-knockout cells display synthetic lethality with the chemotherapeutic agent, cisplatin. Remarkably, the ‘traffic-light reporter’ system revealed that CDYL1 mainly promotes homology-directed repair (HDR) of DSBs in vivo. In addition, following DNA damage induction, CDYL1 depletion causes persistent G2/M arrest and alters H2AX and replication protein A (RPA2) phosphorylation. 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. 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. 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. Here, we describe a previously unrecognized role of chromodomain Y-like (CDYL1) protein in fortifying double-strand break (DSB)-induced transcription repression and repair. DNA damage induction is accompanied by transient transcription repression. Cells have evolved DNA damage response (DDR) to repair DNA lesions and thus preserving genomic stability and impeding carcinogenesis.
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