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PARP1 exhibits enhanced association and catalytic efficiency with γH2A.X-nucleosome

Author

Listed:
  • Deepti Sharma

    (Nanyang Technological University)

  • Louis Falco

    (Nanyang Technological University)

  • Sivaraman Padavattan

    (Nanyang Technological University
    National Institute of Mental Health and Neurosciences)

  • Chang Rao

    (Nanyang Technological University)

  • Susana Geifman-Shochat

    (Nanyang Technological University
    Nanyang Technological University)

  • Chuan-Fa Liu

    (Nanyang Technological University
    Nanyang Technological University)

  • Curt A. Davey

    (Nanyang Technological University
    Nanyang Technological University)

Abstract

The poly(ADP-ribose) polymerase, PARP1, plays a key role in maintaining genomic integrity by detecting DNA damage and mediating repair. γH2A.X is the primary histone marker for DNA double-strand breaks and PARP1 localizes to H2A.X-enriched chromatin damage sites, but the basis for this association is not clear. We characterize the kinetics of PARP1 binding to a variety of nucleosomes harbouring DNA double-strand breaks, which reveal that PARP1 associates faster with (γ)H2A.X- versus H2A-nucleosomes, resulting in a higher affinity for the former, which is maximal for γH2A.X-nucleosome that is also the activator eliciting the greatest poly-ADP-ribosylation catalytic efficiency. The enhanced activities with γH2A.X-nucleosome coincide with increased accessibility of the DNA termini resulting from the H2A.X-Ser139 phosphorylation. Indeed, H2A- and (γ)H2A.X-nucleosomes have distinct stability characteristics, which are rationalized by mutational analysis and (γ)H2A.X-nucleosome core crystal structures. This suggests that the γH2A.X epigenetic marker directly facilitates DNA repair by stabilizing PARP1 association and promoting catalysis.

Suggested Citation

  • Deepti Sharma & Louis Falco & Sivaraman Padavattan & Chang Rao & Susana Geifman-Shochat & Chuan-Fa Liu & Curt A. Davey, 2019. "PARP1 exhibits enhanced association and catalytic efficiency with γH2A.X-nucleosome," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13641-0
    DOI: 10.1038/s41467-019-13641-0
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