POGZ promotes homology-directed DNA repair in an HP1-dependent manner
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ABSTRACT:
SUBMITTER: Mr. John Heath
PROVIDER: S-SCDT-EMBOR-2020-51041V1 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:The heterochromatin protein HP1 plays a central role in the maintenance of genome stability but little is known about how HP1 is controlled. Here, we show that the zinc finger protein POGZ promotes the presence of HP1 at DNA double-strand breaks (DSBs) in human cells. POGZ depletion delays the resolution of DSBs and sensitizes cells to different DNA-damaging agents, including cisplatin and talazoparib. Mechanistically, POGZ promotes homology-directed DNA repair by retaining the BRCA1/BARD1 complex at DSBs in an HP1-dependent manner. In vivo CRISPR inactivation of Pogz is embryonically lethal. Pogz haploinsufficiency (Pogz+ /delta) results in developmental delay, impaired intellectual abilities, hyperactive behaviour and a compromised humoral immune response in mice, recapitulating the main clinical features of the White Sutton syndrome (WHSUS). Pogz+ /delta mice are further radiosensitive and accumulate DSBs in diverse tissues, including the spleen and brain. Altogether, our findings identify POGZ as an important player in homology-directed DNA repair both in vitro and in vivo.
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Project description:Heterochromatin protein 1 paralogs (HP1?, ? and ? in mammals) are not only central in heterochromatin organization, but have also been linked to transcriptional activation at euchromatic regions, maintenance of telomere stability and, most recently, to the DNA damage response (DDR). However, how HP1 proteins contribute to the DDR at a molecular level, and whether HP1 paralogs within the same organism, as well as their respective orthologs, have overlapping or unique roles in the DDR, remain to be elucidated. Herein, we have combined the analysis of the efficiency and kinetics of recruitment of key repair proteins to sites of DNA damage with specific DNA repair assays to demonstrate that human HP1 paralogs differentially modulate homology-directed repair (HDR) pathways, including homologous recombination (HR) and single-strand annealing (SSA). We find that while HP1? and ? stimulate HR and SSA, HP1? has an inhibitory role. In addition, we show that the stimulatory role of HP1? and ? in HDR is linked to the DNA-end resection step of DNA breaks, through the promotion of RPA loading and phosphorylation at damage sites. Altogether, our findings provide mechanistic insight into how human HP1 proteins participate in the recombination process, emerging as important chromatin regulators during HDR.
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