POGZ promotes homology-directed DNA repair in an HP1-dependent manner

被引：14

作者：

Heath, John ^{[1
,2
]}

Cheyou, Estelle Simo ^{[1
,3
]}

Findlay, Steven ^{[1
,2
]}

Luo, Vincent M. ^{[1
,4
]}

Carpio, Edgar Pinedo ^{[1
,2
]}

Lee, Jeesan ^{[1
]}

Djerir, Billel ^{[5
]}

Chen, Xiaoru ^{[1
]}

Morin, Theo ^{[5
]}

Lebeau, Benjamin ^{[1
,2
]}

Karam, Martin ^{[1
,2
]}

Bagci, Halil ^{[6
,7
,10
]}

Grapton, Damien ^{[1
]}

Ursini-Siegel, Josie ^{[1
,2
,3
]}

Cote, Jean-Francois ^{[6
,7
,8
,9
]}

Witcher, Michael ^{[1
,2
]}

Richard, Stephane ^{[1
,3
]}

Marechal, Alexandre ^{[5
]}

Orthwein, Alexandre ^{[1
,2
,3
,4
]}

机构：

[1] Jewish Gen Hosp, Segal Canc Ctr, Lady Davis Inst Med Res, Montreal, PQ, Canada

[2] McGill Univ, Div Expt Med, Montreal, PQ, Canada

[3] McGill Univ, Gerald Bronfman Dept Oncol, Montreal, PQ, Canada

[4] McGill Univ, Dept Microbiol & Immunol, Montreal, PQ, Canada

[5] Univ Sherbrooke, Dept Biol, Sherbrooke, PQ, Canada

[6] Inst Reche Clin Montreal IRCM, Montreal, PQ, Canada

[7] McGill Univ, Dept Anat & Cell Biol, Montreal, PQ, Canada

[8] Univ Montreal, Dept Biochim & Med Mol, Montreal, PQ, Canada

[9] Univ Montreal, Dept Med, Programmes Biol Mol, Montreal, PQ, Canada

[10] Swiss Fed Inst Technol, Inst Biochem, Zurich, Switzerland

来源：

EMBO REPORTS | 2022年 / 23卷 / 01期

基金：

加拿大自然科学与工程研究理事会;

关键词：

DNA double-strand break; homologous recombination; HP1; POGZ; white Sutton syndrome; DOUBLE-STRAND BREAKS; DAMAGE RESPONSE; HETEROCHROMATIN PROTEIN-1; HISTONE H3; CHROMATIN CHANGES; COMET ASSAY; 53BP1; HP1; BRCA1; METHYLATION;

D O I：

10.15252/embr.202051041

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页数：23

共 85 条

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