The BRCA1-Interacting Protein Abraxas Is Required for Genomic Stability and Tumor Suppression

• Published in: Cell reports (Cambridge) 2014-08, Vol.8 (3), p.807-817
• Main Authors: Castillo, Andy, Paul, Atanu, Sun, Baohua, Huang, Ting Hsiang, Wang, Yucai, Yazinski, Stephanie A., Tyler, Jessica, Li, Lei, You, M. James, Zou, Lee, Yao, Jun, Wang, Bin
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Animals; BRCA1 Protein - chemistry; BRCA1 Protein - metabolism; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Carrier Proteins - genetics; Carrier Proteins - metabolism; DNA Repair; Female; Genomic Instability; Germ-Line Mutation; HEK293 Cells; Homozygote; Humans; Mice; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; Protein Binding; Protein Structure, Tertiary
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2014.06.050

Germline mutations of BRCA1 confer hereditary susceptibility to breast and ovarian cancer. However, somatic mutation of BRCA1 is infrequent in sporadic breast cancers. The BRCA1 protein C terminus (BRCT) domains interact with multiple proteins and are required for BRCA1’s tumor-suppressor function. In this study, we demonstrated that Abraxas, a BRCA1 BRCT domain-interacting protein, plays a role in tumor suppression. Abraxas exerts its function through binding to BRCA1 to regulate DNA repair and maintain genome stability. Both homozygous and heterozygous Abraxas knockout mice exhibited decreased survival and increased tumor incidence. The gene encoding Abraxas suffers from gene copy loss and somatic mutations in multiple human cancers including breast, ovarian, and endometrial cancers, suggesting that mutation and loss of function of Abraxas may contribute to tumor development in human patients. [Display omitted] •Abraxas is a haploinsufficient tumor-suppressor gene•Abraxas deficiency causes defective DNA repair and genetic instability•Abraxas-BRCA1 interaction is crucial for DNA repair and genomic stability•Loss of Abraxas function by somatic mutation and gene copy loss in human cancer Abraxas is a BRCA1 BRCT domain-interacting protein. Analyzing an Abraxas-deficient mouse model, Castillo et al. now demonstrate that Abraxas is a tumor suppressor gene and show that the interaction of Abraxas and BRCA1 is critical for Abraxas’ function in DNA repair and maintenance of genome stability. In addition, the Abraxas gene exhibits gene copy loss, reduced expression, and somatic mutations in multiple human cancers including breast, ovarian, and endometrial cancers.