Journal
EMBO JOURNAL
Volume 26, Issue 22, Pages 4768-4776Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.emboj.7601894
Keywords
DNA repair; ERCC1; NMR; nucleotide excision repair; XPA
Categories
Funding
- NIAID NIH HHS [P30 AI060354] Funding Source: Medline
- NIGMS NIH HHS [R01 GM052504, GM52504] Funding Source: Medline
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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.
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