PARP1 regulates RECQL4 recruitment for DNA double-strand break repair

RecQ helicases, highly conserved proteins with pivotal roles in DNA replication, DNA repair, and homologous recombination, are crucial for maintaining genomic integrity. Mutations in RECQL4 have been associated with various human diseases, including Rothmund-Thomson syndrome. RECQL4 is involved in regulating major DNA repair pathways, such as homologous recombination (HR) and non-homologous end repair (NHEJ). RECQL4 has a more prominent single-strand DNA annealing activity than helicase activity. Its recruitment to DNA damage and the precise role of its DNA annealing activity in DNA repair is unclear. This study reveals that PARP1 interacts with RECQL4, enhancing its single-stranded DNA (ssDNA) strand annealing activity. PARP1 specifically promotes - RECQL4-PARylation at both its N- and C-terminal regions, promoting RECQL4’s recruitment to DNA double-strand break (DSB). Inhibition or depletion of PARP1 significantly diminishes RECQL4 recruitment and occupancy at specific DSB sites on chromosomes. RECQL4 actively displaces replication protein A (RPA) from ssDNA, promoting microhomology annealing in vitro . Further, depletion of PARP1 or RECQL4 substantially impacts classical-NHEJ (c-NHEJ) and alternative-NHEJ (alt-NHEJ)-mediated DSB repair. Consequently, the combined activities of PARP1 and RECQL4 modulate DNA repair.