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BRCA1/BARD1 site-specific ubiquitylation of nucleosomal H2A is directed by BARD1

Mutations in BRCA1/BARD1’s E3 ubiquitin ligase RING domains predispose carriers to breast and ovarian cancers. We present the first structure of the BRCA1/BARD1 RING heterodimer with the E2 enzyme UbcH5c bound to its cellular target, the nucleosome, along with biochemical data that explain how the c...

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Autores principales: Witus, Samuel R., Burrell, Anika L., Farrell, Daniel P., Kang, Jianming, Wang, Meiling, Hansen, Jesse M., Pravat, Alex, Tuttle, Lisa M., Stewart, Mikaela D., Brzovic, Peter S., Chatterjee, Champak, Zhao, Weixing, DiMaio, Frank, Kollman, Justin M., Klevit, Rachel E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007219/
https://www.ncbi.nlm.nih.gov/pubmed/33589814
http://dx.doi.org/10.1038/s41594-020-00556-4
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author Witus, Samuel R.
Burrell, Anika L.
Farrell, Daniel P.
Kang, Jianming
Wang, Meiling
Hansen, Jesse M.
Pravat, Alex
Tuttle, Lisa M.
Stewart, Mikaela D.
Brzovic, Peter S.
Chatterjee, Champak
Zhao, Weixing
DiMaio, Frank
Kollman, Justin M.
Klevit, Rachel E.
author_facet Witus, Samuel R.
Burrell, Anika L.
Farrell, Daniel P.
Kang, Jianming
Wang, Meiling
Hansen, Jesse M.
Pravat, Alex
Tuttle, Lisa M.
Stewart, Mikaela D.
Brzovic, Peter S.
Chatterjee, Champak
Zhao, Weixing
DiMaio, Frank
Kollman, Justin M.
Klevit, Rachel E.
author_sort Witus, Samuel R.
collection PubMed
description Mutations in BRCA1/BARD1’s E3 ubiquitin ligase RING domains predispose carriers to breast and ovarian cancers. We present the first structure of the BRCA1/BARD1 RING heterodimer with the E2 enzyme UbcH5c bound to its cellular target, the nucleosome, along with biochemical data that explain how the complex selectively ubiquitylates lysines 125/127/129 in the flexible C-terminal tail of H2A in a fully human system. The structure reveals that a novel BARD1-histone interface couples to a repositioning of UbcH5c compared to the structurally similar PRC1 E3 ligase Ring1b/Bmi1 that ubiquitylates H2A Lys119 in nucleosomes. This interface is sensitive to both H3 Lys79 methylation status and mutations found in cancer patients. Furthermore, NMR reveals an unexpected mode of E3-mediated substrate regulation through modulation of dynamics in the C-terminal tail of H2A. Our findings provide insight into how E3 ligases preferentially target nearby lysine residues in nucleosomes by a steric occlusion and distancing mechanism.
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spelling pubmed-80072192021-08-15 BRCA1/BARD1 site-specific ubiquitylation of nucleosomal H2A is directed by BARD1 Witus, Samuel R. Burrell, Anika L. Farrell, Daniel P. Kang, Jianming Wang, Meiling Hansen, Jesse M. Pravat, Alex Tuttle, Lisa M. Stewart, Mikaela D. Brzovic, Peter S. Chatterjee, Champak Zhao, Weixing DiMaio, Frank Kollman, Justin M. Klevit, Rachel E. Nat Struct Mol Biol Article Mutations in BRCA1/BARD1’s E3 ubiquitin ligase RING domains predispose carriers to breast and ovarian cancers. We present the first structure of the BRCA1/BARD1 RING heterodimer with the E2 enzyme UbcH5c bound to its cellular target, the nucleosome, along with biochemical data that explain how the complex selectively ubiquitylates lysines 125/127/129 in the flexible C-terminal tail of H2A in a fully human system. The structure reveals that a novel BARD1-histone interface couples to a repositioning of UbcH5c compared to the structurally similar PRC1 E3 ligase Ring1b/Bmi1 that ubiquitylates H2A Lys119 in nucleosomes. This interface is sensitive to both H3 Lys79 methylation status and mutations found in cancer patients. Furthermore, NMR reveals an unexpected mode of E3-mediated substrate regulation through modulation of dynamics in the C-terminal tail of H2A. Our findings provide insight into how E3 ligases preferentially target nearby lysine residues in nucleosomes by a steric occlusion and distancing mechanism. 2021-02-15 2021-03 /pmc/articles/PMC8007219/ /pubmed/33589814 http://dx.doi.org/10.1038/s41594-020-00556-4 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Witus, Samuel R.
Burrell, Anika L.
Farrell, Daniel P.
Kang, Jianming
Wang, Meiling
Hansen, Jesse M.
Pravat, Alex
Tuttle, Lisa M.
Stewart, Mikaela D.
Brzovic, Peter S.
Chatterjee, Champak
Zhao, Weixing
DiMaio, Frank
Kollman, Justin M.
Klevit, Rachel E.
BRCA1/BARD1 site-specific ubiquitylation of nucleosomal H2A is directed by BARD1
title BRCA1/BARD1 site-specific ubiquitylation of nucleosomal H2A is directed by BARD1
title_full BRCA1/BARD1 site-specific ubiquitylation of nucleosomal H2A is directed by BARD1
title_fullStr BRCA1/BARD1 site-specific ubiquitylation of nucleosomal H2A is directed by BARD1
title_full_unstemmed BRCA1/BARD1 site-specific ubiquitylation of nucleosomal H2A is directed by BARD1
title_short BRCA1/BARD1 site-specific ubiquitylation of nucleosomal H2A is directed by BARD1
title_sort brca1/bard1 site-specific ubiquitylation of nucleosomal h2a is directed by bard1
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007219/
https://www.ncbi.nlm.nih.gov/pubmed/33589814
http://dx.doi.org/10.1038/s41594-020-00556-4
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