CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair

• Published in: Nature Vol. 434; no. 7033; pp. 598 - 604
• Main Authors: West, Stephen C, Esashi, Fumiko, Christ, Nicole, Gannon, Julian, Liu, Yilun, Hunt, Tim, Jasin, Maria
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 31.03.2005; Nature Publishing Group
• Subjects: Amino Acid Sequence; Animals; Biological and medical sciences; BRCA2 Protein - chemistry; BRCA2 Protein - genetics; BRCA2 Protein - metabolism; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cell division; Cell Line; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cellular biology; Chromosome aberrations; Cyclin-Dependent Kinases - metabolism; Deoxyribonucleic acid; DNA; DNA Damage - genetics; DNA Repair - genetics; DNA-Binding Proteins - metabolism; Enzymes; Fundamental and applied biological sciences. Psychology; Genetics; Humans; Medical genetics; Medical sciences; Molecular and cellular biology; Molecular Sequence Data; Mutation; Nuclear Localization Signals; Phosphorylation; Protein Binding; Rad51 Recombinase; Recombination, Genetic - genetics; Sequence Deletion - genetics; Phosphorylation; Homologous recombination; Cyclin; Breast cancer; Malignant tumor; Carcinogenesis; Mechanism; Mammary gland diseases; Double stranded DNA; BRCA2 gene; Cyclin-dependent protein kinase; Predisposition; Early; Mutation; Repair; Tumor suppressor gene
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature03404

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.