A synthetic lethal siRNA screen identifying genes mediating sensitivity to a PARP inhibitor

被引：256

作者：

Turner, Nicholas C. ^{[1
]}

Lord, Christopher J. ^{[1
]}

Iorns, Elizabeth ^{[1
]}

Brough, Rachel ^{[1
]}

Swift, Sally ^{[1
]}

Elliott, Richard ^{[1
]}

Rayter, Sydonia ^{[1
]}

Tutt, Andrew N. ^{[1
,2
]}

Ashworth, Alan ^{[1
]}

机构：

[1] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England

[2] Kings Coll London, Sch Med, Breakthrough Breast Canc Res Unit, London, England

来源：

EMBO JOURNAL | 2008年 / 27卷 / 09期

关键词：

CDK5; cell cycle; DNA repair; poly(ADP) ribose; polymerase; RNAi screen;

D O I：

10.1038/emboj.2008.61

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：

Inhibitors of poly (ADP-ribose)-polymerase-1 (PARP) are highly lethal to cells with deficiencies in BRCA1, BRCA2 or other components of the homologous recombination pathway. This has led to PARP inhibitors entering clinical trials as a potential therapy for cancer in carriers of BRCA1 and BRCA2 mutations. To discover new determinants of sensitivity to these drugs, we performed a PARP-inhibitor synthetic lethal short interfering RNA (siRNA) screen. We identified a number of kinases whose silencing strongly sensitised to PARP inhibitor, including cyclin-dependent kinase 5 (CDK5), MAPK12, PLK3, PNKP, STK22c and STK36. How CDK5 silencing mediates sensitivity was investigated. Previously, CDK5 has been suggested to be active only in a neuronal context, but here we show that CDK5 is required in non-neuronal cells for the DNA-damage response and, in particular, intra-S and G(2)/M cell-cycle checkpoints. These results highlight the potential of synthetic lethal siRNA screens with chemical inhibitors to define new determinants of sensitivity and potential therapeutic targets.

引用

页码：1368 / 1377

页数：10