Crucial roles of the BRCA1-BARD1 E3 ubiquitin ligase activity in homology-directed DNA repair

Meiling Wang; Wenjing Li; Nozomi Tomimatsu; Corey H. Yu; Jae Hoon Ji; Salvador Alejo; Samuel R. Witus; Dauren Alimbetov; O'Taveon T. Fitzgerald; Bo Wu; Qijing Wang; Yuxin Huang; Yaqi Gan; Felix Dong; Youngho Kwon; Gangadhara R. Sareddy; Tyler J. Curiel; Amyn A. Habib; Robert Hromas; Carolina dos Santos Passos; Tingting Yao; Dmitri N. Ivanov; Peter S. Brzovic; Sandeep Burma; Rachel E. Klevit; Weixing Zhao

doi:10.1016/j.molcel.2023.09.015

Crucial roles of the BRCA1-BARD1 E3 ubiquitin ligase activity in homology-directed DNA repair

Meiling Wang, Wenjing Li, Nozomi Tomimatsu, Corey H. Yu, Jae Hoon Ji, Salvador Alejo, Samuel R. Witus, Dauren Alimbetov, O'Taveon T. Fitzgerald, Bo Wu, Qijing Wang, Yuxin Huang, Yaqi Gan, Felix Dong, Youngho Kwon, Gangadhara R. Sareddy, Tyler J. Curiel, Amyn A. Habib, Robert Hromas, Carolina dos Santos PassosTingting Yao, Dmitri N. Ivanov, Peter S. Brzovic, Sandeep Burma, Rachel E. Klevit, Weixing Zhao

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

The tumor-suppressor breast cancer 1 (BRCA1) in complex with BRCA1-associated really interesting new gene (RING) domain 1 (BARD1) is a RING-type ubiquitin E3 ligase that modifies nucleosomal histone and other substrates. The importance of BRCA1-BARD1 E3 activity in tumor suppression remains highly controversial, mainly stemming from studying mutant ligase-deficient BRCA1-BARD1 species that we show here still retain significant ligase activity. Using full-length BRCA1-BARD1, we establish robust BRCA1-BARD1-mediated ubiquitylation with specificity, uncover multiple modes of activity modulation, and construct a truly ligase-null variant and a variant specifically impaired in targeting nucleosomal histones. Cells expressing either of these BRCA1-BARD1 separation-of-function alleles are hypersensitive to DNA-damaging agents. Furthermore, we demonstrate that BRCA1-BARD1 ligase is not only required for DNA resection during homology-directed repair (HDR) but also contributes to later stages for HDR completion. Altogether, our findings reveal crucial, previously unrecognized roles of BRCA1-BARD1 ligase activity in genome repair via HDR, settle prior controversies regarding BRCA1-BARD1 ligase functions, and catalyze new efforts to uncover substrates related to tumor suppression.

Original language	English (US)
Pages (from-to)	3679-3691.e8
Journal	Molecular cell
Volume	83
Issue number	20
DOIs	https://doi.org/10.1016/j.molcel.2023.09.015
State	Published - Oct 19 2023
Externally published	Yes

Keywords

BARD1
BRCA1
DNA damage response
DNA end resection
HDR
histone
homology-directed repair
later stages for HDR completion
substrates
tumor suppression
ubiquitin E3 ligase

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2023.09.015

Cite this

Wang, M., Li, W., Tomimatsu, N., Yu, C. H., Ji, J. H., Alejo, S., Witus, S. R., Alimbetov, D., Fitzgerald, OT. T., Wu, B., Wang, Q., Huang, Y., Gan, Y., Dong, F., Kwon, Y., Sareddy, G. R., Curiel, T. J., Habib, A. A., Hromas, R., ... Zhao, W. (2023). Crucial roles of the BRCA1-BARD1 E3 ubiquitin ligase activity in homology-directed DNA repair. Molecular cell, 83(20), 3679-3691.e8. https://doi.org/10.1016/j.molcel.2023.09.015

Wang, M, Li, W, Tomimatsu, N, Yu, CH, Ji, JH, Alejo, S, Witus, SR, Alimbetov, D, Fitzgerald, OTT, Wu, B, Wang, Q, Huang, Y, Gan, Y, Dong, F, Kwon, Y, Sareddy, GR, Curiel, TJ, Habib, AA, Hromas, R, dos Santos Passos, C, Yao, T, Ivanov, DN, Brzovic, PS, Burma, S, Klevit, RE & Zhao, W 2023, 'Crucial roles of the BRCA1-BARD1 E3 ubiquitin ligase activity in homology-directed DNA repair', Molecular cell, vol. 83, no. 20, pp. 3679-3691.e8. https://doi.org/10.1016/j.molcel.2023.09.015

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title = "Crucial roles of the BRCA1-BARD1 E3 ubiquitin ligase activity in homology-directed DNA repair",

abstract = "The tumor-suppressor breast cancer 1 (BRCA1) in complex with BRCA1-associated really interesting new gene (RING) domain 1 (BARD1) is a RING-type ubiquitin E3 ligase that modifies nucleosomal histone and other substrates. The importance of BRCA1-BARD1 E3 activity in tumor suppression remains highly controversial, mainly stemming from studying mutant ligase-deficient BRCA1-BARD1 species that we show here still retain significant ligase activity. Using full-length BRCA1-BARD1, we establish robust BRCA1-BARD1-mediated ubiquitylation with specificity, uncover multiple modes of activity modulation, and construct a truly ligase-null variant and a variant specifically impaired in targeting nucleosomal histones. Cells expressing either of these BRCA1-BARD1 separation-of-function alleles are hypersensitive to DNA-damaging agents. Furthermore, we demonstrate that BRCA1-BARD1 ligase is not only required for DNA resection during homology-directed repair (HDR) but also contributes to later stages for HDR completion. Altogether, our findings reveal crucial, previously unrecognized roles of BRCA1-BARD1 ligase activity in genome repair via HDR, settle prior controversies regarding BRCA1-BARD1 ligase functions, and catalyze new efforts to uncover substrates related to tumor suppression.",

keywords = "BARD1, BRCA1, DNA damage response, DNA end resection, HDR, histone, homology-directed repair, later stages for HDR completion, substrates, tumor suppression, ubiquitin E3 ligase",

author = "Meiling Wang and Wenjing Li and Nozomi Tomimatsu and Yu, {Corey H.} and Ji, {Jae Hoon} and Salvador Alejo and Witus, {Samuel R.} and Dauren Alimbetov and Fitzgerald, {O'Taveon T.} and Bo Wu and Qijing Wang and Yuxin Huang and Yaqi Gan and Felix Dong and Youngho Kwon and Sareddy, {Gangadhara R.} and Curiel, {Tyler J.} and Habib, {Amyn A.} and Robert Hromas and {dos Santos Passos}, Carolina and Tingting Yao and Ivanov, {Dmitri N.} and Brzovic, {Peter S.} and Sandeep Burma and Klevit, {Rachel E.} and Weixing Zhao",

note = "Publisher Copyright: {\textcopyright} 2023",

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doi = "10.1016/j.molcel.2023.09.015",

language = "English (US)",

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T1 - Crucial roles of the BRCA1-BARD1 E3 ubiquitin ligase activity in homology-directed DNA repair

AU - Wang, Meiling

AU - Li, Wenjing

AU - Tomimatsu, Nozomi

AU - Yu, Corey H.

AU - Ji, Jae Hoon

AU - Alejo, Salvador

AU - Witus, Samuel R.

AU - Alimbetov, Dauren

AU - Fitzgerald, O'Taveon T.

AU - Wu, Bo

AU - Wang, Qijing

AU - Huang, Yuxin

AU - Gan, Yaqi

AU - Dong, Felix

AU - Kwon, Youngho

AU - Sareddy, Gangadhara R.

AU - Curiel, Tyler J.

AU - Habib, Amyn A.

AU - Hromas, Robert

AU - dos Santos Passos, Carolina

AU - Yao, Tingting

AU - Ivanov, Dmitri N.

AU - Brzovic, Peter S.

AU - Burma, Sandeep

AU - Klevit, Rachel E.

AU - Zhao, Weixing

PY - 2023/10/19

Y1 - 2023/10/19

N2 - The tumor-suppressor breast cancer 1 (BRCA1) in complex with BRCA1-associated really interesting new gene (RING) domain 1 (BARD1) is a RING-type ubiquitin E3 ligase that modifies nucleosomal histone and other substrates. The importance of BRCA1-BARD1 E3 activity in tumor suppression remains highly controversial, mainly stemming from studying mutant ligase-deficient BRCA1-BARD1 species that we show here still retain significant ligase activity. Using full-length BRCA1-BARD1, we establish robust BRCA1-BARD1-mediated ubiquitylation with specificity, uncover multiple modes of activity modulation, and construct a truly ligase-null variant and a variant specifically impaired in targeting nucleosomal histones. Cells expressing either of these BRCA1-BARD1 separation-of-function alleles are hypersensitive to DNA-damaging agents. Furthermore, we demonstrate that BRCA1-BARD1 ligase is not only required for DNA resection during homology-directed repair (HDR) but also contributes to later stages for HDR completion. Altogether, our findings reveal crucial, previously unrecognized roles of BRCA1-BARD1 ligase activity in genome repair via HDR, settle prior controversies regarding BRCA1-BARD1 ligase functions, and catalyze new efforts to uncover substrates related to tumor suppression.

AB - The tumor-suppressor breast cancer 1 (BRCA1) in complex with BRCA1-associated really interesting new gene (RING) domain 1 (BARD1) is a RING-type ubiquitin E3 ligase that modifies nucleosomal histone and other substrates. The importance of BRCA1-BARD1 E3 activity in tumor suppression remains highly controversial, mainly stemming from studying mutant ligase-deficient BRCA1-BARD1 species that we show here still retain significant ligase activity. Using full-length BRCA1-BARD1, we establish robust BRCA1-BARD1-mediated ubiquitylation with specificity, uncover multiple modes of activity modulation, and construct a truly ligase-null variant and a variant specifically impaired in targeting nucleosomal histones. Cells expressing either of these BRCA1-BARD1 separation-of-function alleles are hypersensitive to DNA-damaging agents. Furthermore, we demonstrate that BRCA1-BARD1 ligase is not only required for DNA resection during homology-directed repair (HDR) but also contributes to later stages for HDR completion. Altogether, our findings reveal crucial, previously unrecognized roles of BRCA1-BARD1 ligase activity in genome repair via HDR, settle prior controversies regarding BRCA1-BARD1 ligase functions, and catalyze new efforts to uncover substrates related to tumor suppression.

KW - BARD1

KW - BRCA1

KW - DNA damage response

KW - DNA end resection

KW - HDR

KW - histone

KW - homology-directed repair

KW - later stages for HDR completion

KW - substrates

KW - tumor suppression

KW - ubiquitin E3 ligase

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U2 - 10.1016/j.molcel.2023.09.015

DO - 10.1016/j.molcel.2023.09.015

M3 - Article

C2 - 37797621

AN - SCOPUS:85174070763

SN - 1097-2765

VL - 83

SP - 3679-3691.e8

JO - Molecular cell

JF - Molecular cell

IS - 20

ER -

Crucial roles of the BRCA1-BARD1 E3 ubiquitin ligase activity in homology-directed DNA repair

Abstract

Keywords

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