Ubiquitin ligase ARF-BP1/Mule modulates base excision repair

被引：114

作者：

Parsons, Jason L. ^{[1
]}

Tait, Phillip S. ^{[1
,2
]}

Finch, David ^{[1
]}

Dianova, Irina I. ^{[1
]}

Edelmann, Mariola J. ^{[3
]}

Khoronenkova, Svetlana V. ^{[1
]}

Kessler, Benedikt M. ^{[3
]}

Sharma, Ricky A. ^{[1
]}

McKenna, W. Gillies ^{[1
]}

Dianov, Grigory L. ^{[1
]}

机构：

[1] Univ Oxford, Gray Inst Radiat Oncol & Biol, Oxford OX3 7DQ, Oxon, England

[2] Univ Oxford, Dept Biochem, Oxford OX3 7DQ, Oxon, England

[3] Univ Oxford, Nuffield Dept Clin Med, Ctr Cellular & Mol Physiol, Oxford, England

来源：

EMBO JOURNAL | 2009年 / 28卷 / 20期

基金：

英国医学研究理事会;

关键词：

ARF; base excision repair; DNA polymerase beta; Mule; ubiquitylation; DNA-POLYMERASE-BETA; ARF TUMOR-SUPPRESSOR; OVEREXPRESSION; DAMAGE; INSTABILITY; ACTIVATION; STRESS; CANCER; P53;

D O I：

10.1038/emboj.2009.243

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：

Base excision repair (BER) is the major cellular pathway involved in removal of endogenous/spontaneous DNA lesions. Here, we study the mechanism that controls the steady-state levels of BER enzymes in human cells. By fractionating human cell extract, we purified the E3 ubiquitin ligase Mule (ARF-BP1/HectH9) as an enzyme that can ubiquitylate DNA polymerase beta (Pol beta), the major BER DNA polymerase. We identified lysines 41, 61 and 81 as the major sites of modification and show that replacement of these lysines to arginines leads to increased protein stability. We further show that the cellular levels of Pol beta and its ubiquitylated derivative are modulated by Mule and ARF and siRNA knockdown of Mule leads to accumulation of Pol beta and increased DNA repair. Our findings provide a novel mechanism regulating steady-state levels of BER proteins. The EMBO Journal (2009) 28, 3207-3215. doi:10.1038/emboj.2009.243; Published online 27 August 2009

引用

页码：3207 / 3215

页数：9

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