Evolved histone tail regulates 53BP1 recruitment at damaged chromatin

Jessica L. Kelliher, Melissa L. Folkerts, Kaiyuan V. Shen, Wan Song, Kyle Tengler, Clara M. Stiefel, Seong-Ok Lee, Eloise Dray, Weixing Zhao, Brian Koss, Nicholas R. Pannunzio () and Justin W. Leung ()
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Jessica L. Kelliher: University of Arkansas for Medical Sciences
Melissa L. Folkerts: University of California, Irvine
Kaiyuan V. Shen: University of California, Irvine
Wan Song: University of Texas Health and Science Center
Kyle Tengler: University of Texas Health and Science Center
Clara M. Stiefel: University of Texas Health and Science Center
Seong-Ok Lee: University of Arkansas for Medical Sciences
Eloise Dray: University of Texas Health and Science Center
Weixing Zhao: University of Texas Health and Science Center
Brian Koss: University of Arkansas for Medical Sciences
Nicholas R. Pannunzio: University of California, Irvine
Justin W. Leung: University of Arkansas for Medical Sciences

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract The master DNA damage repair histone protein, H2AX, is essential for orchestrating the recruitment of downstream mediator and effector proteins at damaged chromatin. The phosphorylation of H2AX at S139, γH2AX, is well-studied for its DNA repair function. However, the extended C-terminal tail is not characterized. Here, we define the minimal motif on H2AX for the canonical function in activating the MDC1-RNF8-RNF168 phosphorylation-ubiquitination pathway that is important for recruiting repair proteins, such as 53BP1 and BRCA1. Interestingly, H2AX recruits 53BP1 independently from the MDC1-RNF8-RNF168 pathway through its evolved C-terminal linker region with S139 phosphorylation. Mechanistically, 53BP1 recruitment to damaged chromatin is mediated by the interaction between the H2AX C-terminal tail and the 53BP1 Oligomerization-Tudor domains. Moreover, γH2AX-linker mediated 53BP1 recruitment leads to camptothecin resistance in H2AX knockout cells. Overall, our study uncovers an evolved mechanism within the H2AX C-terminal tail for regulating DNA repair proteins at damaged chromatin.

Date: 2024
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DOI: 10.1038/s41467-024-49071-w

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