Increased risk of lung cancer associated with a functionally impaired polymorphic variant of the human DNA glycosylase NEIL2

被引：40

作者：

Dey, Sanjib

Maiti, Amit K.

Hegde, Muralidhar L. ^{[2
]}

Hegde, Pavana M. ^{[2
]}

Boldogh, Istvan ^{[3
]}

Sarkar, Partha S. ^{[4
]}

Abdel-Rahman, Sherif Z. ^{[5
]}

Sarker, Altaf H. ^{[6
]}

Hang, Bo ^{[6
]}

Xie, Jingwu ^{[7
]}

Tomkinson, Alan E. ^{[8
,9
]}

Zhou, Mian ^{[10
]}

Shen, Binghui ^{[10
]}

Wang, Guanghai ^{[11
]}

Wu, Chen ^{[11
]}

Yu, Dianke ^{[11
]}

Lin, Dongxin ^{[11
]}

Cardenas, Victor

Hazra, Tapas K. ^{[1
,2
]}

机构：

[1] Univ Texas Med Branch, Dept Internal Med, Div Pulm & Crit Care Med, Galveston, TX 77555 USA

[2] Univ Texas Med Branch, Dept Biochem & Mol Biol, Galveston, TX 77555 USA

[3] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 USA

[4] Univ Texas Med Branch, Dept Neurol & Neurosci & Cell Biol, Galveston, TX 77555 USA

[5] Univ Texas Med Branch, Dept Obstet & Gynecol, Galveston, TX 77555 USA

[6] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Berkeley, CA 94720 USA

[7] Indiana Univ Purdue Univ, Dept Pediat, Indianapolis, IN 46202 USA

[8] Univ New Mexico, Ctr Canc, Albuquerque, NM 87131 USA

[9] Dept Internal Med, Albuquerque, NM USA

[10] City Hope Natl Med Ctr, Dept Canc Biol, Duarte, CA USA

[11] Chinese Acad Med Sci, Inst Canc, State Key Lab Mol Oncol, Beijing 100021, Peoples R China

来源：

DNA REPAIR | 2012年 / 11卷 / 06期

关键词：

BER; Lung cancer; NEIL2; SNP; BASE EXCISION-REPAIR; OXIDIZED BASES; SENSITIVE METHOD; DAMAGE; IDENTIFICATION; RADIATION; MUTAGENESIS; EXPRESSION; GENES; CELLS;

D O I：

10.1016/j.dnarep.2012.03.005

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Human NEIL2, one of five oxidized base-specific DNA glycosylases, is unique in preferentially repairing oxidative damage in transcribed genes. Here we show that depletion of NEIL2 causes a 6-7-fold increase in spontaneous mutation frequency in the HPRT gene of the V79 Chinese hamster lung cell line. This prompted us to screen for NEIL2 variants in lung cancer patients' genomic DNA. We identified several polymorphic variants, among which R103Q and R257L were frequently observed in lung cancer patients. We then characterized these variants biochemically, and observed a modest decrease in DNA glycosylase activity relative to the wild type (WT) only with the R257L mutant protein. However, in reconstituted repair assays containing WT NEIL2 or its R257L and R103Q variants together with other DNA base excision repair (BER) proteins (PNKP, Pol beta, Lig III alpha and XRCC1) or using NEIL2-FLAG immunocomplexes, an similar to 5-fold decrease in repair was observed with the R257L variant compared to WT or R103Q NEIL2, apparently due to the R257L mutant's lower affinity for other repair proteins, particularly Pol beta. Notably, increased endogenous DNA damage was observed in NEIL2 variant (R257L)-expressing cells relative to WT cells. Taken together, our results suggest that the decreased DNA repair capacity of the R257L variant can induce mutations that lead to lung cancer development. (C) 2012 Elsevier B.V. All rights reserved.

引用

页码：570 / 578

页数：9

共 51 条

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