Structural Basis of BRCC36 Function in DNA Repair and Immune Regulation
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
Structural Basis of BRCC36 Function in DNA Repair and Immune Regulation. / Rabl, Julius; Bunker, Richard D; Schenk, Andreas D; Cavadini, Simone; Gill, Mark E; Abdulrahman, Wassim; Andrés-Pons, Amparo; Luijsterburg, Martijn S; Ibrahim, Adel F M; Branigan, Emma; Aguirre, Jacob D; Marceau, Aimee H; Guérillon, Claire; Bouwmeester, Tewis; Hassiepen, Ulrich; Peters, Antoine H F M; Renatus, Martin; Gelman, Laurent; Rubin, Seth M; Mailand, Niels; van Attikum, Haico; Hay, Ronald T.; Thomä, Nicolas H.
In: Molecular Cell, Vol. 75, No. 3, 2019, p. 483-497.e9.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Structural Basis of BRCC36 Function in DNA Repair and Immune Regulation
AU - Rabl, Julius
AU - Bunker, Richard D
AU - Schenk, Andreas D
AU - Cavadini, Simone
AU - Gill, Mark E
AU - Abdulrahman, Wassim
AU - Andrés-Pons, Amparo
AU - Luijsterburg, Martijn S
AU - Ibrahim, Adel F M
AU - Branigan, Emma
AU - Aguirre, Jacob D
AU - Marceau, Aimee H
AU - Guérillon, Claire
AU - Bouwmeester, Tewis
AU - Hassiepen, Ulrich
AU - Peters, Antoine H F M
AU - Renatus, Martin
AU - Gelman, Laurent
AU - Rubin, Seth M
AU - Mailand, Niels
AU - van Attikum, Haico
AU - Hay, Ronald T.
AU - Thomä, Nicolas H
PY - 2019
Y1 - 2019
N2 - In mammals, ∼100 deubiquitinases act on ∼20,000 intracellular ubiquitination sites. Deubiquitinases are commonly regarded as constitutively active, with limited regulatory and targeting capacity. The BRCA1-A and BRISC complexes serve in DNA double-strand break repair and immune signaling and contain the lysine-63 linkage-specific BRCC36 subunit that is functionalized by scaffold subunits ABRAXAS and ABRO1, respectively. The molecular basis underlying BRCA1-A and BRISC function is currently unknown. Here we show that in the BRCA1-A complex structure, ABRAXAS integrates the DNA repair protein RAP80 and provides a high-affinity binding site that sequesters the tumor suppressor BRCA1 away from the break site. In the BRISC structure, ABRO1 binds SHMT2α, a metabolic enzyme enabling cancer growth in hypoxic environments, which we find prevents BRCC36 from binding and cleaving ubiquitin chains. Our work explains modularity in the BRCC36 DUB family, with different adaptor subunits conferring diversified targeting and regulatory functions.
AB - In mammals, ∼100 deubiquitinases act on ∼20,000 intracellular ubiquitination sites. Deubiquitinases are commonly regarded as constitutively active, with limited regulatory and targeting capacity. The BRCA1-A and BRISC complexes serve in DNA double-strand break repair and immune signaling and contain the lysine-63 linkage-specific BRCC36 subunit that is functionalized by scaffold subunits ABRAXAS and ABRO1, respectively. The molecular basis underlying BRCA1-A and BRISC function is currently unknown. Here we show that in the BRCA1-A complex structure, ABRAXAS integrates the DNA repair protein RAP80 and provides a high-affinity binding site that sequesters the tumor suppressor BRCA1 away from the break site. In the BRISC structure, ABRO1 binds SHMT2α, a metabolic enzyme enabling cancer growth in hypoxic environments, which we find prevents BRCC36 from binding and cleaving ubiquitin chains. Our work explains modularity in the BRCC36 DUB family, with different adaptor subunits conferring diversified targeting and regulatory functions.
U2 - 10.1016/j.molcel.2019.06.002
DO - 10.1016/j.molcel.2019.06.002
M3 - Journal article
C2 - 31253574
VL - 75
SP - 483-497.e9
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 3
ER -
ID: 227087306