Article
- The EMBO Journal (2007) 26, 4768 - 4776
- doi:10.1038/sj.emboj.7601894
Published online: 18 October 2007
Subject Categories:
Structural basis for the recruitment of ERCC1-XPF to nucleotide excision repair complexes by XPA
Oleg V Tsodikov1,ab, Dmitri Ivanov1,b, Barbara Orelli2, Lidija Staresincic2, Ilana Shoshani2, Robert Oberman4, Orlando D Schärer2,3, Gerhard Wagner1 and Tom Ellenberger4
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
- Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY, USA
- Department of Chemistry, Stony Brook University, Stony Brook, NY, USA
- Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, MO, USA
Correspondence to:
Tom Ellenberger, Department of Biochemistry and Molecular Biophysics, Washington University, Washington University School of Medicine, 660 S Euclid, Campus Box 8231, St Louis, MO 63110, USA. Tel.:+1 314 747 8893; Fax: +1 314 632 4432; E-mail: tome@biochem.wustl.edu
aPresent address: Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA
bThese authors contributed equally to this work
Received 19 May 2007; Accepted 25 September 2007
Abstract
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.
Keywords:
- DNA repair,
- ERCC1,
- NMR,
- nucleotide excision repair,
- XPA
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