PARP1 directly disassembles nucleosomes to regulate DNA repair.

Abstract

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 histone PARylation factor 1 (HPF1), PARP1 generates stable PARylated hexasomes that can facilitate recruitment of DNA- and PAR-dependent factors. In human cells, PARP activity directly drives chromatin accessibility and generates 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 human cells to DNA-damaging treatments, implicating a functional role of PARP1-mediated nucleosome disassembly in DNA repair. Together, our findings support a model in which PARP1 promotes histone eviction to form subnucleosomes that facilitate efficient DNA repair.