PARP2 promotes Break Induced Replication-mediated telomere fragility in response to replication stress.

Autor: Muoio D; UPMC Hillman Cancer Center, University of Pittsburgh Cancer Institute, Department of Pharmacology and Chemical Biology, Pittsburgh, PA, 15213, USA., Laspata N; UPMC Hillman Cancer Center, University of Pittsburgh Cancer Institute, Department of Pharmacology and Chemical Biology, Pittsburgh, PA, 15213, USA.; Department of Biochemistry and Molecular Biology, Thomas Jefferson University, 233S. 10th street, Philadelphia, PA, 19107, USA., Dannenberg RL; Department of Chemistry, The Pennsylvania State University, University park, State College, PA, 16802, USA., Curry C; Department of Biochemistry and Molecular Biology, Thomas Jefferson University, 233S. 10th street, Philadelphia, PA, 19107, USA., Darkoa-Larbi S; Department of Biochemistry and Molecular Biology, Thomas Jefferson University, 233S. 10th street, Philadelphia, PA, 19107, USA., Hedglin M; Department of Chemistry, The Pennsylvania State University, University park, State College, PA, 16802, USA., Uttam S; Department of Computational and Systems Biology, UPMC Hillman Cancer Center, University of Pittsburgh, 5117 Centre Avenue, Pittsburgh, PA, 15213, USA., Fouquerel E; UPMC Hillman Cancer Center, University of Pittsburgh Cancer Institute, Department of Pharmacology and Chemical Biology, Pittsburgh, PA, 15213, USA. Elf115@pitt.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Apr 02; Vol. 15 (1), pp. 2857. Date of Electronic Publication: 2024 Apr 02.
DOI: 10.1038/s41467-024-47222-7
Abstrakt: PARP2 is a DNA-dependent ADP-ribosyl transferase (ARTs) enzyme with Poly(ADP-ribosyl)ation activity that is triggered by DNA breaks. It plays a role in the Base Excision Repair pathway, where it has overlapping functions with PARP1. However, additional roles for PARP2 have emerged in the response of cells to replication stress. In this study, we demonstrate that PARP2 promotes replication stress-induced telomere fragility and prevents telomere loss following chronic induction of oxidative DNA lesions and BLM helicase depletion. Telomere fragility results from the activity of the break-induced replication pathway (BIR). During this process, PARP2 promotes DNA end resection, strand invasion and BIR-dependent mitotic DNA synthesis by orchestrating POLD3 recruitment and activity. Our study has identified a role for PARP2 in the response to replication stress. This finding may lead to the development of therapeutic approaches that target DNA-dependent ART enzymes, particularly in cancer cells with high levels of replication stress.
(© 2024. The Author(s).)
Databáze: MEDLINE
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