Structural basis for the recruitment of ERCC1-XPF to nucleotide excision repair complexes by XPA

The nucleotide excision repair (NER) pathway corrects DNA damage caused by sunlight, environmental mutagens and certain antitumor agents. This multistep DNA repair reaction operates by the sequential assembly of protein factors at sites of DNA damage. The efficient recognition of DNA damage and its...

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Bibliographic Details
Published in:The EMBO journal 2007-11, Vol.26 (22), p.4768-4776
Main Authors: Tsodikov, Oleg V, Ivanov, Dmitri, Orelli, Barbara, Staresincic, Lidija, Shoshani, Ilana, Oberman, Robert, Schärer, Orlando D, Wagner, Gerhard, Ellenberger, Tom
Format: Article
Language:English
Subjects:
Binding Sites
Deoxyribonucleic acid
DNA
DNA - metabolism
DNA damage
DNA Repair
DNA-Binding Proteins - chemistry
DNA-Binding Proteins - metabolism
ERCC1
Escherichia coli - genetics
Escherichia coli - metabolism
HeLa Cells
Humans
Molecular biology
Molecular structure
Mutagens
Mutation
NMR
nucleotide excision repair
Peptides
Peptides - chemistry
Peptides - genetics
Peptides - metabolism
Protein Conformation
Proteins
Sunlight
Xeroderma Pigmentosum Group A Protein - chemistry
Xeroderma Pigmentosum Group A Protein - genetics
Xeroderma Pigmentosum Group A Protein - metabolism
XPA
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Summary:The nucleotide excision repair (NER) pathway corrects DNA damage caused by sunlight, environmental mutagens and certain antitumor agents. This multistep DNA repair reaction operates by the sequential assembly of protein factors at sites of DNA damage. The efficient recognition of DNA damage and its repair are orchestrated by specific protein–protein and protein–DNA interactions within NER complexes. We have investigated an essential protein–protein interaction of the NER pathway, the binding of the XPA protein to the ERCC1 subunit of the repair endonuclease ERCC1‐XPF. The structure of ERCC1 in complex with an XPA peptide shows that only a small region of XPA interacts with ERCC1 to form a stable complex exhibiting submicromolar binding affinity. However, this XPA peptide is a potent inhibitor of NER activity in a cell‐free assay, blocking the excision of a cisplatin adduct from DNA. The structure of the peptide inhibitor bound to its target site reveals a binding interface that is amenable to the development of small molecule peptidomimetics that could be used to modulate NER repair activities in vivo .
ISSN:0261-4189
1460-2075
DOI:10.1038/sj.emboj.7601894