Homologous-recombination-deficient tumours are dependent on Polθ-mediated repair

被引：674

作者：

Ceccaldi, Raphael ^{[1
]}

Liu, Jessica C. ^{[1
,2
,3
]}

Amunugama, Ravindra ^{[4
]}

Hajdu, Ildiko ^{[5
]}

Primack, Benjamin ^{[1
]}

Petalcorin, Mark I. R. ^{[6
]}

O'Connor, Kevin W. ^{[1
]}

Konstantinopoulos, Panagiotis A. ^{[7
]}

Elledge, Stephen J. ^{[5
]}

Boulton, Simon J. ^{[6
]}

Yusufzai, Timur ^{[1
,2
]}

D'Andrea, Alan D. ^{[1
]}

机构：

[1] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02215 USA

[2] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02215 USA

[3] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA

[4] Harvard Univ, Sch Med, Howard Hughes Med Inst, Dept Biol Chem & Mol Pharmacol, Boston, MA 02215 USA

[5] Brigham & Womens Hosp, Howard Hughes Med Inst, Div Genet, Boston, MA 02215 USA

[6] London Res Inst, Canc Res UK, DNA Damage Response Lab, S Mimms EN6 3LD, Herts, England

[7] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol,Med Gynecol Oncol Program, Boston, MA 02215 USA

来源：

NATURE | 2015年 / 518卷 / 7538期

基金：

英国惠康基金;

关键词：

STRAND BREAK REPAIR; DNA-DAMAGE; OVARIAN-CANCER; GENOMIC INSTABILITY; HEMATOPOIETIC STEM; FANCONI-ANEMIA; HUMAN-CELLS; POLYMERASE; PATHWAY; CHEMOTHERAPY;

D O I：

10.1038/nature14184

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Large-scale genomic studies have shown that half of epithelial ovarian cancers (EOCs) have alterations in genes regulating homologous recombination (HR) repair(1). Loss of HR accounts for the genomic instability of EOCs and for their cellular hyper-dependence on alternative poly-ADP ribose polymerase (PARP)-mediated DNA repair mechanisms(2-5). Previous studies have implicated the DNA polymerase theta (Pol theta also known as POLQ, encoded by POLQ) 6 in a pathway required for the repair of DNA double-strand breaks(7-9), referred to as the error-prone microhomology-mediated end-joining (MMEJ) pathway(10-13). Whether Pol theta interacts with canonical DNA repair pathways to prevent genomic instability remains unknown. Here we report an inverse correlation between HR activity and Pol theta expression in EOCs. Knockdown of Pol theta in HR-proficient cells upregulates HR activity and RAD51 nucleofilament assembly, while knockdown of Pol theta in HR-deficient EOCs enhances cell death. Consistent with these results, genetic inactivation of an HR gene (Fancd2) and Polq in mice results in embryonic lethality. Moreover, Pol theta contains RAD51 binding motifs and it blocks RAD51-mediated recombination. Our results reveal a synthetic lethal relationship between the HR pathway and Pol theta-mediated repair in EOCs, and identify Pol theta as a novel druggable target for cancer therapy.

引用

页码：258 / U306

页数：21

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