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

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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. Structural studies of the BRCA1-A and BRISC complexes reveal a common enzymatic core that is functionalized by complex-specific proteins. BRCA1-A localizes to DNA double-strand breaks, sequesters BRCA1, and suppresses DNA resection. BRISC regulates protein degradation by the endosomal-lysosomal pathway through deubiquitination and is inhibited by the metabolic enzyme SHMT2.

Original language	English
Journal	Molecular Cell
Volume	75
Issue number	3
Pages (from-to)	483-497.e9
Number of pages	25
ISSN	1097-2765
DOIs	https://doi.org/10.1016/j.molcel.2019.06.002
Publication status	Published - 8 Aug 2019

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Structural Basis of BRCC36 Function in DNA Repair and Immune RegulationFinal published version, 5.63 MBLicence: CC BY-NC-ND

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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. https://doi.org/10.1016/j.molcel.2019.06.002

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

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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. Structural studies of the BRCA1-A and BRISC complexes reveal a common enzymatic core that is functionalized by complex-specific proteins. BRCA1-A localizes to DNA double-strand breaks, sequesters BRCA1, and suppresses DNA resection. BRISC regulates protein degradation by the endosomal-lysosomal pathway through deubiquitination and is inhibited by the metabolic enzyme SHMT2.",

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",

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language = "English",

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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. Structural studies of the BRCA1-A and BRISC complexes reveal a common enzymatic core that is functionalized by complex-specific proteins. BRCA1-A localizes to DNA double-strand breaks, sequesters BRCA1, and suppresses DNA resection. BRISC regulates protein degradation by the endosomal-lysosomal pathway through deubiquitination and is inhibited by the metabolic enzyme SHMT2.

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. Structural studies of the BRCA1-A and BRISC complexes reveal a common enzymatic core that is functionalized by complex-specific proteins. BRCA1-A localizes to DNA double-strand breaks, sequesters BRCA1, and suppresses DNA resection. BRISC regulates protein degradation by the endosomal-lysosomal pathway through deubiquitination and is inhibited by the metabolic enzyme SHMT2.

U2 - 10.1016/j.molcel.2019.06.002

DO - 10.1016/j.molcel.2019.06.002

M3 - Journal 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

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