Histone H2A variants alpha1-extension helix directs RNF168-mediated ubiquitination

Jessica L. Kelliher, Kirk L. West, Qingguo Gong and Justin W. C. Leung ()
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Jessica L. Kelliher: University of Arkansas for Medical Sciences
Kirk L. West: University of Arkansas for Medical Sciences
Qingguo Gong: University of Science and Technology of China
Justin W. C. Leung: University of Arkansas for Medical Sciences

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract Histone ubiquitination plays an important role in the DNA damage response (DDR) pathway. RNF168 catalyzes H2A and H2AX ubiquitination on lysine 13/15 (K13/K15) upon DNA damage and promotes the accrual of downstream repair factors at damaged chromatin. Here, we report that RNF168 ubiquitinates the non-canonical H2A variants H2AZ and macroH2A1/2 at the divergent N-terminal tail lysine residue. In addition to their evolutionarily conserved nucleosome acidic patch, we identify the positively charged alpha1-extension helix as essential for RNF168-mediated ubiquitination of H2A variants. Moreover, mutation of the RNF168 UMI (UIM- and MIU-related UBD) hydrophilic acidic residues abolishes RNF168-mediated ubiquitination as well as 53BP1 and BRCA1 ionizing radiation-induced foci formation. Our results reveal a juxtaposed bipartite electrostatic interaction utilized by the nucleosome to direct RNF168 orientation towards the target lysine residues in proximity to the H2A alpha1-extension helix, which plays an important role in the DDR pathway.

Date: 2020
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DOI: 10.1038/s41467-020-16307-4

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