Xrcc1 is Phosphorylated by Dna-dependent Protein Kinase in Response to Dna Damage.
From: Département Intégrité du génome de l’UMR 7175, CNRS, Ecole Supérieure de Biotechnologie de Strasbourg, Boulevard S. Brant, BP 10413, F-67412 Illkirch Cedex, France.
Nucleic acids research
- Publish Date: 2006
- ISSN: 1362-4962
- Volume: 34
- Issue: 1
- Pages: 32-41
- Medium: Internet
- Language: English
- Citation (JAMA): Lévy Nicolas, Martz Adeline, Bresson Anne, et al. Xrcc1 is Phosphorylated by Dna-dependent Protein Kinase in Response to Dna Damage.. Nucleic Acids Res. 2006;34:32-41
Abstract
The two BRCT domains (BRCT1 and BRCT2) of XRCC1 mediate a network of protein-protein interactions with several key factors of the DNA single-strand breaks (SSBs) and base damage repair pathways. BRCT1 is required for the immediate poly(ADP-ribose)-dependent recruitment of XRCC1 to DNA breaks and is essential for survival after DNA damage. To better understand the biological role of XRCC1 in the processing of DNA ends, a search for the BRCT1 domain-associated proteins was performed by mass spectrometry of GST-BRCT1 pulled-down proteins from HeLa cell extracts. Here, we report that the double-strand break (DSB) repair heterotrimeric complex DNA-PK interacts with the BRCT1 domain of XRCC1 and phosphorylates this domain at serine 371 after ionizing irradiation. This caused XRCC1 dimer dissociation. The XRCC1 R399Q variant allele did not affect this phosphorylation. We also show that XRCC1 strongly stimulates the phosphorylation of p53-Ser15 by DNA-PK. The pseudo phosphorylated S371D mutant was a much weaker stimulator of DNA-PK activity whereas the non-phosphorylable mutant S371L endowed with a DNA-PK stimulating capacity failed to fully rescue the DSB repair defect of XRCC1-deficient EM9 rodent cells. The functional association between XRCC1 and DNA-PK in response to IR provides the first evidence for their involvement in a common DSB repair pathway.
Mesh Headings (Keywords): Animals, Binding Sites, Cricetinae, DNA Damage, DNA Repair, DNA-Activated Protein Kinase, DNA-Binding Proteins, Dimerization, Hela Cells, Humans, Mass Spectrometry, Phosphorylation, Protein Structure, Tertiary, Radiation, Ionizing, Serine
Check for Full Text / PubMed Unique Identifier (PMID): 16397295
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