Reduced Nuclease Activity of Apurinic/Apyrimidinic Endonuclease ( APE1)Variants on Nucleosomes IDENTIFICATION OF ACCESS RESIDUES

被引:27
|
作者
Hinz, John M. [1 ]
Mao, Peng [1 ]
McNeill, Daniel R. [2 ]
Wilson, David M., III [2 ]
机构
[1] Washington State Univ, Sch Mol Biosci, Pullman, WA 99164 USA
[2] NIA, Lab Mol Gerontol, IRP, NIH, Baltimore, MD 21224 USA
基金
美国国家卫生研究院;
关键词
BASE EXCISION-REPAIR; URACIL-DNA GLYCOSYLASE; GLUCOCORTICOID RESPONSE ELEMENT; CORE PARTICLES; MAJOR HUMAN; BINDING; APE1; ACCESSIBILITY; COORDINATION; PROTEIN;
D O I
10.1074/jbc.M115.665547
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
Non-coding apurinic/apyrimidinic (AP) sites are generated at high frequency in genomic DNA via spontaneous hydrolytic, damage-induced or enzyme-mediated base release. AP endonuclease 1 (APE1) is the predominant mammalian enzyme responsible for initiating removal of mutagenic and cytotoxic abasic lesions as part of the base excision repair (BER) pathway. We have examined here the ability of wild-type (WT) and a collection of variant/mutant APE1 proteins to cleave at an AP site within a nucleosome core particle. Our studies indicate that, in comparison to the WT protein and other variant/mutant enzymes, the incision activity of the tumor-associated variant R237C and the rare population variant G241R are uniquely hypersensitive to nucleosome complexes in the vicinity of the AP site. This defect appears to stem from an abnormal interaction of R237C and G241R with abasic DNA substrates, but is not simply due to a DNA binding defect, as the site-specific APE1 mutant Y128A, which displays markedly reduced AP-DNA complex stability, did not exhibit a similar hypersensitivity to nucleosome structures. Notably, this incision defect of R237C and G241R was observed on a pre-assembled DNA glycosylase.AP-DNA complex as well. Our results suggest that the BER enzyme, APE1, has acquired distinct surface residues that permit efficient processing of AP sites within the context of protein-DNA complexes independent of classic chromatin remodeling mechanisms.
引用
收藏
页码:21067 / 21075
页数:9
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