CDYL1 fosters double-strand break-induced transcription silencing and promotes homology-directed repair

Abstract

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.

WWP2 ubiquitylates RNA polymerase II for DNA-PK-dependent transcription arrest and repair at DNA breaks

“…This process, which remained unaffected by ATM inhibition (Pankotai et al 2012), is mediated by the ubiquitylation and eviction of RNAPII. In contrast, DSBs generated in close proximity to a gene lead to its transient repression through ATM-or PARP-1-mediated chromatin remodeling, which induces a chromatin context that is repressive for transcription (Shanbhag et al 2010;Kakarougkas et al 2014;Gong et al 2015Gong et al , 2017Ui et al 2015;Ui and Yasui 2016;Awwad et al 2017;Abu-Zhayia et al 2018;Gong and Miller 2018).…”

“…Finally, PARP1 triggers the recruitment of chromodomain protein Y-like (CDYL1), which negatively regulates transcription through histone H3K27 methylation (Abu-Zhayia et al 2018). While NELF promotes DSB repair via both NHEJ and HR, KDM5a, ZMYND8-NuRD, and CDYL1 promote DSB repair through HR only (Gong et al 2015(Gong et al , 2017Abu-Zhayia et al 2018). Together, these studies revealed that ATM and PARP1 silence transcription of genes that flank DSBs by triggering extensive chromatin remodeling around the damage, thereby promoting efficient repair by NHEJ and HR.…”

“…Moreover, PARP1 mediates recruitment of the NELF complex (Awwad et al 2017), a negative regulator of transcription, which has been described to regulate RNAPII pausing at promoters shortly after transcription initiation (Li et al 2013). Finally, PARP1 triggers the recruitment of chromodomain protein Y-like (CDYL1), which negatively regulates transcription through histone H3K27 methylation (Abu-Zhayia et al 2018). While NELF promotes DSB repair via both NHEJ and HR, KDM5a, ZMYND8-NuRD, and CDYL1 promote DSB repair through HR only (Gong et al 2015(Gong et al , 2017Abu-Zhayia et al 2018).…”

PARylation During Transcription: Insights into the Fine-Tuning Mechanism and Regulation

“…During DNA damage-induced transcription silencing, PARP1 facilitates the recruitment of the polycomb repressive complex 1 and 2 (PRC1 and PRC2), ensuring the proper chromatin structure and transcription arrest at the damaged sites [44,47]. Moreover, the chromodomain Y like (CDYL) protein interacts with PRC2 in a PARP-dependent manner [48,49]. During DSB-induced transcription silencing, PARP1 promotes the recruitment of KRAB-associated protein-1 (KAP-1), heterochromatin protein 1 (HP1), and suppressor of variegation 3-9 homolog 1 (SUV39H1) ( Figure 3A) [50].…”

Structural basis for the binding selectivity of human CDY chromodomains

“…Not surprisingly, both CDYL and G9a are upregulated in hepatocellular carcinoma (HCC), but not in non-cancerous liver tissues 20 . CDYL1 also associates with chromatin assembly factor 1 (CAF1) and the MCM complex, and recruits histone H3K9/27 methyltransferases G9a, SETDB1, and PRC2 to the replication forks for transmission of repressive chromatin marks during DNA replication 21 , or to DNA double-strand break (DSB) sites for transcriptional silencing and promotion of homology-directed DNA repair (HDR) 22 .…”