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Multiple DNA Binding Domains Mediate the Function of the ERCC1-XPF Protein in Nucleotide Excision Repair

Author(s)
Su, YanOrelli, BarbaraMadireddy, AdvaithaNiedernhofer, Laura J.Schaerer, Orlando D.
Issued Date
2012-06
DOI
10.1074/jbc.M111.337899
URI
https://scholarworks.unist.ac.kr/handle/201301/21253
Fulltext
http://www.jbc.org/content/287/26/21846
Citation
JOURNAL OF BIOLOGICAL CHEMISTRY, v.287, no.26, pp.21846 - 21855
Abstract
ERCC1-XPF is a heterodimeric, structure-specific endonuclease that cleaves single-stranded/double-stranded DNA junctions and has roles in nucleotide excision repair (NER), interstrand crosslink (ICL) repair, homologous recombination, and possibly other pathways. In NER, ERCC1-XPF is recruited to DNA lesions by interaction with XPA and incises the DNA 5' to the lesion. We studied the role of the four C-terminal DNA binding domains in mediating NER activity and cleavage of model substrates. We found that mutations in the helix-hairpin-helix domain of ERCC1 and the nuclease domain of XPF abolished cleavage activity on model substrates. Interestingly, mutations in multiple DNA binding domains were needed to significantly diminish NER activity in vitro and in vivo, suggesting that interactions with proteins in the NER incision complex can compensate for some defects in DNA binding. Mutations in DNA binding domains of ERCC1-XPF render cells more sensitive to the crosslinking agent mitomycin C than to ultraviolet radiation, suggesting that the ICL repair function of ERCC1-XPF requires tighter substrate binding than NER. Our studies show that multiple domains of ERCC1-XPF contribute to substrate binding, and are consistent with models of NER suggesting that multiple weak protein-DNA and protein-protein interactions drive progression through the pathway. Our findings are discussed in the context of structural studies of individual domains of ERCC1-XPF and of its role in multiple DNA repair pathways
Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
ISSN
0021-9258
Keyword
STRUCTURE-SPECIFIC ENDONUCLEASESSTRUCTURE-SPECIFIC NUCLEASESHOLLIDAY JUNCTION RESOLVASEFANCONI-ANEMIAXERODERMA-PIGMENTOSUMCRYSTAL-STRUCTURESTRUCTURAL BASISDUAL-INCISIONDAMAGED DNAMECHANISMS

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