AI Article Synopsis
- - The RING domains of the BRCA1/BARD1 E3 ubiquitin ligase are linked to an increased risk of breast and ovarian cancers due to mutations.
- - The study reveals the structure of the BRCA1/BARD1 complex with the E2 enzyme UbcH5c and how it selectively modifies specific lysines in the histone H2A's tails in human cells.
- - A new interface between BARD1 and histone, influenced by H3 methylation and certain cancer mutations, was identified, explaining how E3 ligases target lysine residues using a unique mechanism of steric occlusion and distance.
Article Abstract
Mutations in the E3 ubiquitin ligase RING domains of BRCA1/BARD1 predispose carriers to breast and ovarian cancers. We present the 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 and 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 individuals with cancer. 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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Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007219 | PMC |
| http://dx.doi.org/10.1038/s41594-020-00556-4 | DOI Listing |
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