PARP1 directly disassembles nucleosomes to regulate DNA repair of Verma and Zhu et al.
Description
Upon DNA damage, chromatin remodeling is rapidly initiated to promote chromatin accessibility. Although this enhanced accessibility has been linked to poly(ADP-ribose) polymerase (PARP) activity, how cells overcome the nucleosome barrier remains unclear. We discovered that PARP1 directly and asymmetrically evicts histone dimers proximal to DNA strand breaks from nucleosomes to generate oriented hexasomes. In the presence of HPF1, PARP1 generates stable PARylated hexasomes that can facilitate recruitment of DNAand PAR-dependent factors. In cells, PARP activity is both required and sufficient to drive chromatin accessibility and the recruitment of repair factors via subnucleosomal species. Unexpectedly, we identified the C-terminal tail of histone H2A, a motif harboring recurrent cancer-associated mutations, as a critical determinant of efficient PARP1-mediated nucleosome disassembly. Deletion of the H2A tail sensitizes cells to DNA-damaging treatments, implicating a functional role of PARP1-mediated nucleosome disassembly in DNA repair. Together, our findings suggest that PARP1 directly drives histone eviction to form subnucleosomes that facilitate efficient DNA repair.
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Institutions
- St. Jude Children's Research HospitalTennessee, Memphis
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Funders
- National Institute of General Medical SciencesNational Institutes of HealthBethesdaGrant ID: R35GM160211