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

Deepti Sharma, Louis Falco, Sivaraman Padavattan, Chang Rao, Susana Geifman-Shochat, Chuan-Fa Liu and Curt A. Davey ()
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Deepti Sharma: Nanyang Technological University
Louis Falco: Nanyang Technological University
Sivaraman Padavattan: Nanyang Technological University
Chang Rao: Nanyang Technological University
Susana Geifman-Shochat: Nanyang Technological University
Chuan-Fa Liu: Nanyang Technological University
Curt A. Davey: Nanyang Technological University

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-13641-0

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