CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair Journal Article
| Authors: | Esashi, F.; Christ, N.; Cannon, J.; Liu, Y.; Hunt, T.; Jasin, M.; West, S. C. |
| Article Title: | CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair |
| Abstract: | Inherited mutations in BRCA2 are associated with a predisposition to early-onset breast cancers. The underlying basis of tumorigenesis is thought to be linked to defects in DNA double-strand break repair by homologous recombination. Here we show that the carboxy-terminal region of BRCA2, which interacts directly with the essential recombination protein RAD51, contains a site (serine 3291; S3291) that is phosphorylated by cyclin-dependent kinases. Phosphorylation of S3291 is low in S phase when recombination is active, but increases as cells progress towards mitosis. This modification blocks C-terminal interactions between BRCA2 and RAD51. However, DNA damage overcomes cell cycle regulation by decreasing S3291 phosphorylation and stimulating interactions with RAD51. These results indicate that S3291 phosphorylation might provide a molecular switch to regulate RAD51 recombination activity, providing new insight into why BRCA2 C-terminal deletions lead to radiation sensitivity and cancer predisposition. |
| Keywords: | controlled study; protein phosphorylation; dna binding protein; gene mutation; human cell; gene deletion; genetics; dna-binding proteins; sequence deletion; molecular genetics; mitosis; animal; metabolism; animals; dna damage; homologous recombination; cell cycle; cell cycle s phase; dna repair; cancer susceptibility; breast cancer; serine; carboxy terminal sequence; protein protein interaction; cell line; protein binding; pathology; breast neoplasms; phosphorylation; brca2 protein; carcinogenesis; tumorigenesis; chemistry; dna; double stranded dna; genetic recombination; regulatory mechanism; amino acid sequence; molecular sequence data; genetic engineering; tumors; early cancer; recombination, genetic; breast tumor; radiosensitivity; cyclin-dependent kinases; cyclin dependent kinase; genetic predisposition; nuclear localization signal; medicine; enzymes; genetic linkage; rad51 protein; nuclear localization signals; mutations; rad51 recombinase; cells; rad51 protein, human; radiation sensitivity; recombination activity |
| Journal Title: | Nature |
| Volume: | 434 |
| Issue: | 7033 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2005-03-31 |
| Start Page: | 598 |
| End Page: | 604 |
| Language: | English |
| DOI: | 10.1038/nature03404 |
| PUBMED: | 15800615 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 188" - "Export Date: 24 October 2012" - "CODEN: NATUA" - "Source: Scopus" |
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