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
Faithful transmission or restoration of epigenetic information such as repressive histone modifications through generations is crit- ical for the maintenance of cell identity. We report here that chromodomain Y-like p...Faithful transmission or restoration of epigenetic information such as repressive histone modifications through generations is crit- ical for the maintenance of cell identity. We report here that chromodomain Y-like protein （CDYL）, a chromodomain-containing transcription corepressor, is physically associated with chromatin assembly factor 1 （CAF-1） and the repiicative heUcase MCM complex. We showed that CDYL bridges CAF-1 and MCM, facilitating histone transfer and deposition during DNA replication. We demonstrated that CDYI. recruits histone-modifying enzymes G9a, SETDB1, and EZH2 to replication forks, leading to the addition of H3Kgme2/3 and H3K27me2/3 on newly deposited histone H3. Significantly, depletion of CDYL impedes early S phase progres- sion and sensitizes cells to DNA damage. Our data indicate that CDYL plays an important role in the transmission/restoration of repressive histone marks, thereby preserving the epigenetic landscape for the maintenance of cell identity.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.
文摘Faithful transmission or restoration of epigenetic information such as repressive histone modifications through generations is crit- ical for the maintenance of cell identity. We report here that chromodomain Y-like protein （CDYL）, a chromodomain-containing transcription corepressor, is physically associated with chromatin assembly factor 1 （CAF-1） and the repiicative heUcase MCM complex. We showed that CDYL bridges CAF-1 and MCM, facilitating histone transfer and deposition during DNA replication. We demonstrated that CDYI. recruits histone-modifying enzymes G9a, SETDB1, and EZH2 to replication forks, leading to the addition of H3Kgme2/3 and H3K27me2/3 on newly deposited histone H3. Significantly, depletion of CDYL impedes early S phase progres- sion and sensitizes cells to DNA damage. Our data indicate that CDYL plays an important role in the transmission/restoration of repressive histone marks, thereby preserving the epigenetic landscape for the maintenance of cell identity.
