Structural Basis of BRCC36 Function in DNA Repair and Immune Regulation

Julius Rabl; Richard D. Bunker; Andreas D. Schenk; Simone Cavadini; Mark E. Gill; Wassim Abdulrahman; Amparo Andrés-Pons; Martijn S. Luijsterburg; Adel F. M. Ibrahim; Emma Branigan; Jacob D. Aguirre; Aimee H. Marceau; Claire Guérillon; Tewis Bouwmeester; Ulrich Hassiepen; Antoine H. F. M. Peters; Martin Renatus; Laurent Gelman; Seth M. Rubin; Niels Mailand; Haico van Attikum; Ronald T. Hay; Nicolas H. Thomä

doi:10.1016/j.molcel.2019.06.002

Structural Basis of BRCC36 Function in DNA Repair and Immune Regulation

Julius Rabl, Richard D. Bunker, Andreas D. Schenk, Simone Cavadini, Mark E. Gill, Wassim Abdulrahman, Amparo Andrés-Pons, Martijn S. Luijsterburg, Adel F. M. Ibrahim, Emma Branigan, Jacob D. Aguirre, Aimee H. Marceau, Claire Guérillon, Tewis Bouwmeester, Ulrich Hassiepen, Antoine H. F. M. Peters, Martin Renatus, Laurent Gelman, Seth M. Rubin, Niels MailandHaico van Attikum, Ronald T. Hay, Nicolas H. Thomä (Lead / Corresponding author)

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Abstract

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.

Original language	English
Pages (from-to)	483-497.e9
Number of pages	15
Journal	Molecular Cell
Volume	75
Issue number	3
Early online date	25 Jun 2019
DOIs	https://doi.org/10.1016/j.molcel.2019.06.002
Publication status	Published - 8 Aug 2019

Keywords

BRCA1-A
BRISC
DNA repair
SHMT2
deubiquitination
regulation
ubiquitin signaling

ASJC Scopus subject areas

Molecular Biology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.molcel.2019.06.002Licence: CC BY-NC-ND

Final Published VersionFinal published version, 5.67 MBLicence: CC BY-NC-ND

http://www.sciencedirect.com/science/article/pii/S1097276519304356

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Rabl, J., Bunker, R. D., Schenk, A. D., Cavadini, S., Gill, M. E., Abdulrahman, W., Andrés-Pons, A., Luijsterburg, M. S., Ibrahim, A. F. M., Branigan, E., Aguirre, J. D., Marceau, A. H., Guérillon, C., Bouwmeester, T., Hassiepen, U., Peters, A. H. F. M., Renatus, M., Gelman, L., Rubin, S. M., ... Thomä, N. H. (2019). Structural Basis of BRCC36 Function in DNA Repair and Immune Regulation. Molecular Cell, 75(3), 483-497.e9. Advance online publication. https://doi.org/10.1016/j.molcel.2019.06.002

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title = "Structural Basis of BRCC36 Function in DNA Repair and Immune Regulation",

abstract = "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.",

keywords = "BRCA1-A, BRISC, DNA repair, SHMT2, deubiquitination, regulation, ubiquitin signaling",

author = "Julius Rabl and Bunker, {Richard D.} and Schenk, {Andreas D.} and Simone Cavadini and Gill, {Mark E.} and Wassim Abdulrahman and Amparo Andr{\'e}s-Pons and Luijsterburg, {Martijn S.} and Ibrahim, {Adel F. M.} and Emma Branigan and Aguirre, {Jacob D.} and Marceau, {Aimee H.} and Claire Gu{\'e}rillon and Tewis Bouwmeester and Ulrich Hassiepen and Peters, {Antoine H. F. M.} and Martin Renatus and Laurent Gelman and Rubin, {Seth M.} and Niels Mailand and {van Attikum}, Haico and Hay, {Ronald T.} and Thom{\"a}, {Nicolas H.}",

year = "2019",

month = aug,

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doi = "10.1016/j.molcel.2019.06.002",

language = "English",

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pages = "483--497.e9",

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Rabl, J, Bunker, RD, Schenk, AD, Cavadini, S, Gill, ME, Abdulrahman, W, Andrés-Pons, A, Luijsterburg, MS, Ibrahim, AFM , Branigan, E, Aguirre, JD, Marceau, AH, Guérillon, C, Bouwmeester, T, Hassiepen, U, Peters, AHFM, Renatus, M, Gelman, L, Rubin, SM, Mailand, N, van Attikum, H, Hay, RT & Thomä, NH 2019, 'Structural Basis of BRCC36 Function in DNA Repair and Immune Regulation', Molecular Cell, vol. 75, no. 3, pp. 483-497.e9. https://doi.org/10.1016/j.molcel.2019.06.002

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 - 2019/8/8

Y1 - 2019/8/8

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.

KW - BRCA1-A

KW - BRISC

KW - DNA repair

KW - SHMT2

KW - deubiquitination

KW - regulation

KW - ubiquitin signaling

UR - http://www.scopus.com/inward/record.url?scp=85071349142&partnerID=8YFLogxK

U2 - 10.1016/j.molcel.2019.06.002

DO - 10.1016/j.molcel.2019.06.002

M3 - Article

C2 - 31253574

SN - 1097-2765

VL - 75

SP - 483-497.e9

JO - Molecular Cell

JF - Molecular Cell

IS - 3

ER -

Structural Basis of BRCC36 Function in DNA Repair and Immune Regulation

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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Determining the Role and Mechanism of Action of SUMO Targeted Ubiquitin Ligase RNF4 in Maintaining Genome Integrity (Senior Investigator Award)

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Structural Basis of BRCC36 Function in DNA Repair and Immune Regulation

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

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Determining the Role and Mechanism of Action of SUMO Targeted Ubiquitin Ligase RNF4 in Maintaining Genome Integrity (Senior Investigator Award)

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