The BRCA1 ring domain is essential for DNA damage repair and G2/M checkpoint activation

The BRCA1 (breast cancer 1, early onset) tumor suppressor gene is involved in a variety of cellular pathways, and is an essential factor for normal DNA repair by homologous recombination. The BRCA1 protein has a number of conserved domains, including a coiled-coil domain, two BRCT domains and an N-terminal RING (Really Interesting New Gene) domain. Many cancer-causing mutations have been reported that affect the BRCA1 RING domain, although the exact impact of RING domain mutations on DNA repair is not clear. We characterized a BRCA1-mutant mouse model, BRCA1∆2/∆2 , in which conditional deletion of exon 2 excises a large portion of the RING domain. BRCA1∆2/∆2 cells have a defective G2/M cell cycle checkpoint after IR-induced DNA damage. In addition, BRCA1∆2/∆2 showed a high rate of genomic instability after treatment with agents that cause DNA double strand breaks or DNA interstrand crosslinks. Co-deletion of the 53BP1 (p53 Binding Protein 1) gene rescues some, but not all, phenotypes of mutation of the BRCA1 RING domain. By clarifying the importance of the RING domain in mediating BRCA1 activity, we aim to better understand why patient mutations in the BRCA1 gene cause cancer predisposition and identify new targets for therapeutic intervention.M.S.Includes bibliographical referencesby Ali Naji Ali Al Hamz