RECQL4 requires PARP1 for recruitment to DNA damage, and PARG dePARylation facilitates its associated role in end joining

Abstract

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 and nonhomologous end joining (NHEJ). RECQL4 has more prominent single-strand DNA annealing activity than helicase activity. Its ability to promote DNA damage repair and the precise role of its DNA annealing activity in DNA repair are unclear. Here we demonstrate that PARP1 interacts with RECQL4, increasing its single-stranded DNA strand annealing activity. PARP1 specifically promoted RECQL4 PARylation at both its N- and C-terminal regions, promoting RECQL4 recruitment to DNA double-strand breaks (DSBs). Inhibition or depletion of PARP1 significantly diminished RECQL4 recruitment and occupancy at specific DSB sites on chromosomes. After DNA damage, PARG dePARylated RECQL4 and stimulated its end-joining activity. RECQL4 actively displaced replication protein A from single-stranded DNA, promoting microhomology annealing in vitro. Furthermore, depletion of PARP1 or RECQL4 substantially impacted classical-NHEJ- and alternative-NHEJ-mediated DSB repair. Consequently, the combined activities of PARP1, PARG and RECQL4 modulate DNA repair. Cells have mechanisms to repair DNA damage, which is crucial for preventing diseases such as cancer. The authors wanted to understand how another protein, PARP1, affects the role of RECQL4 in DNA repair. The study involved laboratory experiments using human cells to see how RECQL4 and PARP1 interact. PARP1 helps recruit RECQL4 to sites of DNA damage and enhances its ability to repair DNA by promoting the strand annealing process. However, when RECQL4 is modified by PARP1 through PARylation, its repair activity is reduced. Another protein, PARG, can reverse this modification, restoring the function of RECQL4. The results suggest that the interaction between RECQL4 and PARP1 is important for efficient DNA repair. This understanding could lead to new strategies for treating diseases related to DNA repair defects, such as cancer. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.