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Evolved histone tail regulates 53BP1 recruitment at damaged chromatin

Author

Listed:
  • Jessica L. Kelliher

    (University of Arkansas for Medical Sciences
    University of Arkansas for Medical Sciences)

  • Melissa L. Folkerts

    (University of California, Irvine
    University of California, Irvine)

  • Kaiyuan V. Shen

    (University of California, Irvine
    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
    University of Texas Health and Science Center)

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.

Suggested Citation

  • 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 & Justin W. Le, 2024. "Evolved histone tail regulates 53BP1 recruitment at damaged chromatin," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49071-w
    DOI: 10.1038/s41467-024-49071-w
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    References listed on IDEAS

    as
    1. Jessica L. Kelliher & Kirk L. West & Qingguo Gong & Justin W. C. Leung, 2020. "Histone H2A variants alpha1-extension helix directs RNF168-mediated ubiquitination," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    2. Jordan R. Becker & Gillian Clifford & Clara Bonnet & Anja Groth & Marcus D. Wilson & J. Ross Chapman, 2021. "BARD1 reads H2A lysine 15 ubiquitination to direct homologous recombination," Nature, Nature, vol. 596(7872), pages 433-437, August.
    3. Israel Salguero & Rimma Belotserkovskaya & Julia Coates & Matylda Sczaniecka-Clift & Mukerrem Demir & Satpal Jhujh & Marcus D. Wilson & Stephen P. Jackson, 2019. "MDC1 PST-repeat region promotes histone H2AX-independent chromatin association and DNA damage tolerance," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
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