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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...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2021
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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. |
format | Online Article Text |
id | pubmed-8007219 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
record_format | MEDLINE/PubMed |
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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