DNA Polymerases as Potential Therapeutic Targets for Cancers Deficient in the DNA Mismatch Repair Proteins MSH2 or MLH1

被引：151

作者：

Martin, Sarah A. ^{[1
,2
]}

McCabe, Nuala ^{[1
,2
]}

Mullarkey, Michelle ^{[3
]}

Cummins, Robert ^{[3
]}

Burgess, Darren J. ^{[1
,2
]}

Nakabeppu, Yusaku ^{[4
]}

Oka, Sugako ^{[4
]}

Kay, Elaine ^{[3
]}

Lord, Christopher J. ^{[1
]}

Ashworth, Alan ^{[1
,2
]}

机构：

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

[2] Inst Canc Res, Canc Res UK Gene Funct & Regulat Grp, London SW3 6JB, England

[3] Beaumont Hosp, Educ & Res Ctr, Royal Coll Surg Ireland, Dept Pathol, Dublin 9, Ireland

[4] Kyushu Univ, Med Inst Bioregulat, Div Neurofunct Genom, Dept Neurosci & Immunol, Fukuoka 8128582, Japan

来源：

CANCER CELL | 2010年 / 17卷 / 03期

关键词：

INTERSTRAND CROSS-LINKS; NONPOLYPOSIS COLORECTAL-CANCER; MICROSATELLITE INSTABILITY; TUMOR-CELLS; IN-VITRO; POLY(ADP-RIBOSE) POLYMERASE; MUTATION CARRIERS; OXIDATIVE DAMAGE; GAMMA INHIBITION; DRUG-RESISTANCE;

D O I：

10.1016/j.ccr.2009.12.046

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Synthetic sickness/lethality (SSL) can be exploited to develop therapeutic strategies for cancer. Deficiencies in the tumor suppressor proteins MLH1 and MSH2 have been implicated in cancer. Here we demonstrate that deficiency in MSH2 is SSL with inhibition of the DNA polymerase POLB, whereas deficiency in MLH1 is SSL with DNA polymerase POLG inhibition. Both SSLs led to the accumulation of 8-oxoG oxidative DNA lesions. MSH2/POLB SSL caused nuclear 8-oxoG accumulation, whereas MLH1/POLG SSL led to a rise in mitochondrial 8-oxoG levels. Both SSLs were rescued by silencing the adenine glycosylase MUTYH, suggesting that lethality could be caused by the formation of lethal DNA breaks upon 8-oxoG accumulation. These data suggest targeted, mechanism-based therapeutic approaches.

引用

页码：235 / 248

页数：14

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