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 invol...
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Nature Publishing Group
2025-01-01
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| Series: | Experimental and Molecular Medicine |
| Online Access: | https://doi.org/10.1038/s12276-024-01383-z |
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| author | Mansoor Hussain Prabhat Khadka Komal Pekhale Tomasz Kulikowicz Samuel Gray Alfred May Deborah L. Croteau Vilhelm A. Bohr |
| author_facet | Mansoor Hussain Prabhat Khadka Komal Pekhale Tomasz Kulikowicz Samuel Gray Alfred May Deborah L. Croteau Vilhelm A. Bohr |
| author_sort | Mansoor Hussain |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-8f25cf3cbc5c4e41bbbceeb642c44709 |
| institution | Kabale University |
| issn | 2092-6413 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
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| series | Experimental and Molecular Medicine |
| spelling | doaj-art-8f25cf3cbc5c4e41bbbceeb642c447092025-02-09T12:14:13ZengNature Publishing GroupExperimental and Molecular Medicine2092-64132025-01-0157126428010.1038/s12276-024-01383-zRECQL4 requires PARP1 for recruitment to DNA damage, and PARG dePARylation facilitates its associated role in end joiningMansoor Hussain0Prabhat Khadka1Komal Pekhale2Tomasz Kulikowicz3Samuel Gray4Alfred May5Deborah L. Croteau6Vilhelm A. Bohr7Section on DNA Repair, Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of HealthSection on DNA Repair, Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of HealthSection on DNA Repair, Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of HealthSection on DNA Repair, Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of HealthSection on DNA Repair, Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of HealthSection on DNA Repair, Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of HealthSection on DNA Repair, Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of HealthSection on DNA Repair, Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of HealthAbstract 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.https://doi.org/10.1038/s12276-024-01383-z |
| spellingShingle | Mansoor Hussain Prabhat Khadka Komal Pekhale Tomasz Kulikowicz Samuel Gray Alfred May Deborah L. Croteau Vilhelm A. Bohr RECQL4 requires PARP1 for recruitment to DNA damage, and PARG dePARylation facilitates its associated role in end joining Experimental and Molecular Medicine |
| title | RECQL4 requires PARP1 for recruitment to DNA damage, and PARG dePARylation facilitates its associated role in end joining |
| title_full | RECQL4 requires PARP1 for recruitment to DNA damage, and PARG dePARylation facilitates its associated role in end joining |
| title_fullStr | RECQL4 requires PARP1 for recruitment to DNA damage, and PARG dePARylation facilitates its associated role in end joining |
| title_full_unstemmed | RECQL4 requires PARP1 for recruitment to DNA damage, and PARG dePARylation facilitates its associated role in end joining |
| title_short | RECQL4 requires PARP1 for recruitment to DNA damage, and PARG dePARylation facilitates its associated role in end joining |
| title_sort | recql4 requires parp1 for recruitment to dna damage and parg deparylation facilitates its associated role in end joining |
| url | https://doi.org/10.1038/s12276-024-01383-z |
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