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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217276318   1 MSYREQVLHKQLTRILGVPDLVFLLFSFISTANNSTHALEYVLFRPNRRYNQRISLAIPNLGNTSQQEYKVSSVPNTSQS 80
Cdd:cd23524   105 MSYREQVIHKQLTRILGVPDLVFLLFSFISTANNSTHALEYVLFRPNRRYNQRISLAIPNLGNTSQQEYKVSSVPNTSQN 184

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 2217276318  81 YAKVIKEHGTDFFDKDGVMKDIRAIYQVYNALQEKVQAVCADVEKSERVVESCQAEVNKLRRQITQRKNEK 151
Cdd:cd23524   185 YAKVIKEHGTDFFDKDGVMKDIRAIYQVYNALQEKVQAVCADVEKSERVVESCQAEVNKLKRQITQRKNEK 255

BRISC complex subunit Abraxas 2; 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; BRISC's catalytic subunit is the deubiquitinase (DUB) BRCC36. BRCC36 associates with pseudo-DUB protein Abraxas2, which lacks the essential Zn2+-coordinating residues required for DUB catalytic function. Higher-order association of BRCC36 and Abraxas2 into a dimer of heterodimers (superdimer) is required for BRCC36 DUB activity. 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 in BRISC is activated by assembly due to interaction between Glu30 of BRCC36 and Asn164 in Abraxas 2 which structures the activation loop and positions the catalytic Glu33. The members here include Abraxas 2 domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217276318   1 MSYREQVLHKQLTRILGVPDLVFLLFSFISTANNSTHALEYVLFRPNRRYNQRISLAIPNLGNTSQQEYKVSSVPNTSQS 80
Cdd:cd23524   105 MSYREQVIHKQLTRILGVPDLVFLLFSFISTANNSTHALEYVLFRPNRRYNQRISLAIPNLGNTSQQEYKVSSVPNTSQN 184

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 2217276318  81 YAKVIKEHGTDFFDKDGVMKDIRAIYQVYNALQEKVQAVCADVEKSERVVESCQAEVNKLRRQITQRKNEK 151
Cdd:cd23524   185 YAKVIKEHGTDFFDKDGVMKDIRAIYQVYNALQEKVQAVCADVEKSERVVESCQAEVNKLKRQITQRKNEK 255

BRISC complex subunit Abraxas 2; 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; BRISC's catalytic subunit is the deubiquitinase (DUB) BRCC36. BRCC36 associates with pseudo-DUB protein Abraxas2, which lacks the essential Zn2+-coordinating residues required for DUB catalytic function. Higher-order association of BRCC36 and Abraxas2 into a dimer of heterodimers (superdimer) is required for BRCC36 DUB activity. 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 in BRISC is activated by assembly due to interaction between Glu30 of BRCC36 and Asn164 in Abraxas 2 which structures the activation loop and positions the catalytic Glu33. The members here include Abraxas 2 domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217276318   1 MSYREQVLHKQLTRILGVPDLVFLLFSFISTANNSTHALEYVLFRPNRRYNQRISLAIPNLGNTSQQEYKVSSVPNTSQS 80
Cdd:cd23524   105 MSYREQVIHKQLTRILGVPDLVFLLFSFISTANNSTHALEYVLFRPNRRYNQRISLAIPNLGNTSQQEYKVSSVPNTSQN 184

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 2217276318  81 YAKVIKEHGTDFFDKDGVMKDIRAIYQVYNALQEKVQAVCADVEKSERVVESCQAEVNKLRRQITQRKNEK 151
Cdd:cd23524   185 YAKVIKEHGTDFFDKDGVMKDIRAIYQVYNALQEKVQAVCADVEKSERVVESCQAEVNKLKRQITQRKNEK 255

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217276318   1 MSYREQVLHKQLTRIL---GVPDLVFLLFSFISTANNSTHALEYVLFRPNRRYNQRISLAIPNLGNTSQQEYKVSSVP-- 75
Cdd:cd23519   105 PSLRERAVHKNLLSVLpgdSPKDFLFGLFTASTSDNHSTHSYDYVFYTYNDRSFEPLPLKVVNLGDTSHSEYKLSPTSta 184

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 2217276318  76 NTSQSYAKVIKEHGTDFFDKDGVMKDIRAIYQVYNALQEKVQAVCADVEKSERVVESCQAEVNKLRRQITQRK 148
Cdd:cd23519   185 VTSSTFSSILDSYRSDFVDETGQLQQVDAIEQMYKSLLEKLKSLCEEVSKSEAEVGQLEKEVEQLREKVERKK 257