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PDBsum entry 6h3c
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Signaling protein
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PDB id
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6h3c
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Contents |
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255 a.a.
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258 a.a.
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383 a.a.
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237 a.a.
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440 a.a.
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References listed in PDB file
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Key reference
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Title
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Structural basis of brcc36 function in DNA repair and immune regulation.
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Authors
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J.Rabl,
R.D.Bunker,
A.D.Schenk,
S.Cavadini,
M.E.Gill,
W.Abdulrahman,
A.Andrés-Pons,
M.S.Luijsterburg,
A.F.M.Ibrahim,
E.Branigan,
J.D.Aguirre,
A.H.Marceau,
C.Guérillon,
T.Bouwmeester,
U.Hassiepen,
A.H.F.M.Peters,
M.Renatus,
L.Gelman,
S.M.Rubin,
N.Mailand,
H.Van attikum,
R.T.Hay,
N.H.Thomä.
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Ref.
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Mol Cell, 2019,
75,
483.
[DOI no: ]
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PubMed id
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Abstract
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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.
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