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BRCA1-A complex subunit Abraxas 1 BRCA1-A complex subunit Abraxas 1, also known as ABRA1, FAM175A, and CCDC98, is involved in DNA damage response and double-strand break (DSB) repair and acts as a central scaffold protein that assembles the various components of the complex and mediates the recruitment of BRCA1. The BRCA1-A complex consists of Abraxas 1, BRCC36, BRE, MERIT40, and RAP80, and specifically recognizes 'Lys-63'-linked ubiquitinated histones H2A and H2AX at DNA lesion sites, leading to target the BRCA1-BARD1 heterodimer to sites of DNA damage at DSBs. This complex also possesses deubiquitinase (DUB) activity that specifically removes 'Lys-63'-linked ubiquitin on histones H2A and H2AX; its DUB is BRCC36, which associates with pseudo-DUB protein Abraxas 1 which lacks the essential Zn2+-coordinating residues required for DUB catalytic function. BRCA1-A opposes homologous recombination (HR) by suppressing resection. It has been shown for BIR (break-induced replication), an HR-subtype that involves extensive DNA resection and mutagenic DNA synthesis; that Abraxas 1 inhibits DNA end resection through regulating the levels of SLX4/MUS81 chromatin loading at DSBs in response to Topoisomerase I (TOP1) inhibitor-induced DNA damage. Familial mutations in the BRCA1-A proteins Abraxas 1 and RAP80 predispose carriers to early-onset breast cancer, analogous to mutations in BRCA1 and BRCA2. BRCA1-A requires the tandem ubiquitin (UIM2)- and SUMO-interacting motifs (SIM) in RAP80 and the BRCC36 DUB to function in DNA repair. BRCA1-A recruits BRCA1 by binding its BRCT domains upon phosphorylation of a motif near the C-terminus of Abraxas 1. BRCA1 binding to BRCA1-A sequesters the HR activator BRCA1 about 2-10 kb distal from DNA break sites, which is posited to limit HR. It is currently unclear how BRCA1-A is functionalized and targeted by RAP80 and Abraxas 1 and how BRCA1 is inhibited when bound to the complex. BRCC36 in BRCA1-A is activated by assembly due to interaction between Glu30 of BRCC36 and Asn170 in Abraxas 1 which structures the activation loop and positions the catalytic Glu33. |
Jiyao W et al.(2023). "The conserved domain database in 2023.",