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, ...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.展开更多
基金This work was supported by grants from the Israel Science Foundation OSF, Grant no. 2021242）, the Israel Cancer Association （Grant no. 2019404）, the Binational Science Foundation （Grant no. 2023065）, the Israel Cancer Research Fund （ICRF, Grant no. 2021_762）, and Volkswagen Foundation （Grant no. 2020594）. E.R.A.-Z. and S.W.A. are supported by the Council for Higher Education 19 fellowship for outstanding minority M.Sc. and Ph.D. students, respectively. N.A. is supported by the Neubauer Family Foundation.
文摘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.
