?cl49623: Abraxas-like_domain Superfamily
Abraxas-like domain of BRCA1-A complex subunit Abraxas 1, BRISC complex subunit Abraxas 2, and similar domains found in insects and plants BRCA1-A and BRISC complex subunit BRE (also known as BRISC and BRCA1 A complex member 2; BRCC4; BRCC45) is a core component of both the BRCA1-A and BRISC complexes. BRCA1-A and BRISC are separate complexes with diverging function; they use the same core of subunits to perform very distinct biological tasks, and are found in all vertebrates. 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. The BRCA1-A complex 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. 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 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. BRISC complex subunit Abraxas 2 is also known as ABRO1, FAM175B or KIAA0157. The BRISC complex consists of BRCC36, MERIT40, BRE, and Abraxas 2, and serves cellular stress response and immune signaling functions; it specifically cleaves 'Lys-63'-linked polyubiquitin, leaving the last ubiquitin chain attached to its substrates; In the BRISC complex, Abraxas 2 binds SHMT2a, a metabolic enzyme enabling cancer growth in hypoxic environments, which prevents the BRCC36 from binding and cleaving ubiquitin chains. BRCC36 is the DUB for both BRCA1-A and BRISC. BRCC36 associates with pseudo-DUB proteins (Abraxas 1 in BRCA1-A, Abraxas 2 in BRISC), which lack the essential Zn2+-coordinating residues required for DUB catalytic function. BRCC36 in BRCA1-A and BRISC is activated by assembly due to interaction between Glu30 of BRCC36 and Asn170 in Abraxas 1 and Asn164 in Abraxas 2, respectively, which structures the activation loop and positions the catalytic Glu33, For the BRISC complex it has been shown that higher-order association of BRCC36 and Abraxas2 into a dimer of heterodimers (superdimer) is required for BRCC36 DUB activity. A BRISC complex (containing of BRE/BRCC45, BRCC36, MERIT40, and Abraxas 2/KIAA0157) has been found in insects (Camponotus floridanus) and shown to efficiently degrade K63-linked chains. Homologs of genes encoding components of BRCA1-A and BRISC complexes have been found in plant genomes, including for BRE/BRCC45; plant homologs of BRCC36 have been shown to be involved in DNA repair, and BRCC36-KIAA0157 complexes have been found in Arabidopsis. |
Jiyao W et al.(2023). "The conserved domain database in 2023.",