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bioRxiv · 10.1101/2024.04.09.588726

Histone H3 Orchestrates the Ubiquitination of Nucleosomal H2A by BRCA1/BARD1-UbcH5c Complex

Goldman, A. R.·Shah, T.·Torabifard, H.
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Abstract

The Breast Cancer Associated Protein 1 (BRCA1) is a human tumor suppressor protein that commonly functions as ubiquitin ligase enzyme (E3) in the ubiquitination of the C-terminal H2A. BRCA1 enhances ubiquitin ligase activity by forming a heterodimeric complex with the BRCA1 Associated Ring Domain Protein (BARD1). The BRCA1/BARD1 complex works in concert with the ubiquitin-conjugating enzyme (UbcH5c or E2) to ubiquitinate one of the five lysines of the H2A C-terminal, ultimately promoting the repair of double-stranded DNA breaks. The mutations in the BRCA1-UbcH5c portion of the E3-E2 complex have been linked to breast and ovarian cancer. However, the mechanism of BRCA1/BARD1-UbcH5c complex ubiquitination at H2A is poorly understood, and the ubiquitination of exact lysine is debated. In this study, we sought to expand on the current research on H2A ubiquitination by using all-atom molecular dynamics simulations to model the BRCA1/BARD1-UbcH5c complex with the human ubiquitin protein (Ub). The Ub protein covalently bonds to the active site of E2, resulting in diminished flexibility of the E3-E2 complex with respect to the nucleosome core particle. The results of this study suggest a possible contribution of H3 in determining the preferred orientation of E2-Ub with respect to the H2A C-terminal lysines.

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Goldman, A. R., Shah, T., Torabifard, H.. 2024-04-09. Histone H3 Orchestrates the Ubiquitination of Nucleosomal H2A by BRCA1/BARD1-UbcH5c Complex. https://doi.org/10.1101/2024.04.09.588726

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