The CIP2A-TOPBP1 axis safeguards chromosome stability and is a synthetic lethal target for BRCA-mutated cancer

被引：64

作者：

Adam, Salome ^{[1
]}

Rossi, Silvia Emma ^{[1
]}

Moatti, Nathalie ^{[1
]}

Zompit, Mara De Marco ^{[2
,3
]}

Xue, Yibo ^{[1
]}

Ng, Timothy F. ^{[1
,4
]}

Alvarez-Quilon, Alejandro ^{[1
,5
]}

Desjardins, Jessica ^{[5
]}

Bhaskaran, Vivek ^{[5
]}

Martino, Giovanni ^{[5
]}

Setiaputra, Dheva ^{[1
]}

Noordermeer, Sylvie M. ^{[1
,6
]}

Ohsumi, Toshiro K. ^{[5
]}

Hustedt, Nicole ^{[1
,7
]}

Szilard, Rachel K. ^{[1
]}

Chaudhary, Natasha ^{[1
]}

Munro, Meagan ^{[1
]}

Veloso, Artur ^{[5
]}

Melo, Henrique ^{[1
]}

Yin, Shou Yun ^{[5
]}

Papp, Robert ^{[5
]}

Young, Jordan T. F. ^{[5
]}

Zinda, Michael ^{[5
]}

Stucki, Manuel ^{[2
,3
]}

Durocher, Daniel ^{[1
,4
]}

机构：

[1] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada

[2] Univ Hosp, Dept Gynecol, Schlieren, Switzerland

[3] Univ Zurich, Schlieren, Switzerland

[4] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada

[5] Repare Therapeut, St Laurent, PQ, Canada

[6] Leiden Univ, Dept Human Genet, Med Ctr, Leiden, Netherlands

[7] Lonza AG, Visp, Switzerland

来源：

NATURE CANCER | 2021年 / 2卷 / 12期

基金：

瑞士国家科学基金会;

关键词：

EARLY EMBRYONIC LETHALITY; PROTEIN PHOSPHATASE 2A; HOMOLOGOUS-RECOMBINATION; CELL-CYCLE; DNA; INHIBITOR; CIP2A; DEFICIENCY; ONCOPROTEIN; MUTATIONS;

D O I：

10.1038/s43018-021-00266-w

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Durocher and colleagues identify CIP2A through synthetic lethal CRISPR screens as a key regulator of adaptive feedback mechanisms controlling chromosomal stability arising from accumulated DNA lesions in BRCA-mutated tumor cells. BRCA1/2-mutated cancer cells adapt to the genome instability caused by their deficiency in homologous recombination (HR). Identification of these adaptive mechanisms may provide therapeutic strategies to target tumors caused by the loss of these genes. In the present study, we report genome-scale CRISPR-Cas9 synthetic lethality screens in isogenic pairs of BRCA1- and BRCA2-deficient cells and identify CIP2A as an essential gene in BRCA1- and BRCA2-mutated cells. CIP2A is cytoplasmic in interphase but, in mitosis, accumulates at DNA lesions as part of a complex with TOPBP1, a multifunctional genome stability factor. Unlike PARP inhibition, CIP2A deficiency does not cause accumulation of replication-associated DNA lesions that require HR for their repair. In BRCA-deficient cells, the CIP2A-TOPBP1 complex prevents lethal mis-segregation of acentric chromosomes that arises from impaired DNA synthesis. Finally, physical disruption of the CIP2A-TOPBP1 complex is highly deleterious in BRCA-deficient tumors, indicating that CIP2A represents an attractive synthetic lethal therapeutic target for BRCA1- and BRCA2-mutated cancers.

引用

页码：1357 / +

页数：32

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