دورية أكاديمية
أعرض في EDS

The TIMELESS and PARP1 interaction suppresses replication-associated DNA gap accumulation.

التفاصيل البيبلوغرافية
العنوان: The TIMELESS and PARP1 interaction suppresses replication-associated DNA gap accumulation.
المؤلفون: Saldanha J; Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, NY 11794, USA.; The Graduate program in Genetics, State University of New York at Stony Brook, Stony Brook, NY 11794, USA., Rageul J; Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, NY 11794, USA., Patel JA; Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, NY 11794, USA., Phi AL; Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, NY 11794, USA., Lo N; Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, NY 11794, USA., Park JJ; Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, NY 11794, USA., Kim H; Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, NY 11794, USA.; The Graduate program in Genetics, State University of New York at Stony Brook, Stony Brook, NY 11794, USA.; Stony Brook Cancer Center, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY 11794, USA.
المصدر: Nucleic acids research [Nucleic Acids Res] 2024 Jun 24; Vol. 52 (11), pp. 6424-6440.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE
أسماء مطبوعة: Publication: 1992- : Oxford : Oxford University Press
Original Publication: London, Information Retrieval ltd.
مواضيع طبية MeSH: DNA Replication* , Poly (ADP-Ribose) Polymerase-1*/metabolism , Poly (ADP-Ribose) Polymerase-1*/genetics , DNA, Single-Stranded*/metabolism , DNA, Single-Stranded*/genetics , Cell Cycle Proteins*/metabolism , Cell Cycle Proteins*/genetics, Humans ; Flap Endonucleases/metabolism ; Flap Endonucleases/genetics ; Intracellular Signaling Peptides and Proteins/metabolism ; Intracellular Signaling Peptides and Proteins/genetics ; X-ray Repair Cross Complementing Protein 1/metabolism ; X-ray Repair Cross Complementing Protein 1/genetics ; DNA/metabolism ; DNA/genetics ; DNA Repair ; DNA-Binding Proteins/metabolism ; DNA-Binding Proteins/genetics ; DNA Ligase ATP/metabolism ; DNA Ligase ATP/genetics
مستخلص: TIMELESS (TIM) in the fork protection complex acts as a scaffold of the replisome to prevent its uncoupling and ensure efficient DNA replication fork progression. Nevertheless, its underlying basis for coordinating leading and lagging strand synthesis to limit single-stranded DNA (ssDNA) exposure remains elusive. Here, we demonstrate that acute degradation of TIM at ongoing DNA replication forks induces the accumulation of ssDNA gaps stemming from defective Okazaki fragment (OF) processing. Cells devoid of TIM fail to support the poly(ADP-ribosyl)ation necessary for backing up the canonical OF processing mechanism mediated by LIG1 and FEN1. Consequently, recruitment of XRCC1, a known effector of PARP1-dependent single-strand break repair, to post-replicative ssDNA gaps behind replication forks is impaired. Physical disruption of the TIM-PARP1 complex phenocopies the rapid loss of TIM, indicating that the TIM-PARP1 interaction is critical for the activation of this compensatory pathway. Accordingly, combined deficiency of FEN1 and the TIM-PARP1 interaction leads to synergistic DNA damage and cytotoxicity. We propose that TIM is essential for the engagement of PARP1 to the replisome to coordinate lagging strand synthesis with replication fork progression. Our study identifies TIM as a synthetic lethal target of OF processing enzymes that can be exploited for cancer therapy.
(© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)
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معلومات مُعتمدة: R01 GM144399 United States GM NIGMS NIH HHS; RSG-18-037-DMC American Cancer Society; Breast Cancer Alliance; T32 GM127253 United States GM NIGMS NIH HHS; F31CA278156 United States NH NIH HHS; F31 CA278156 United States CA NCI NIH HHS; American Cancer Society Institutional Research; R01GM144399 United States NH NIH HHS; R01GM144399 United States NH NIH HHS; F31CA278156 United States NH NIH HHS
المشرفين على المادة: EC 2.4.2.30 (Poly (ADP-Ribose) Polymerase-1)
0 (DNA, Single-Stranded)
0 (Cell Cycle Proteins)
EC 3.1.- (Flap Endonucleases)
0 (TIMELESS protein, human)
0 (Intracellular Signaling Peptides and Proteins)
EC 2.4.2.30 (PARP1 protein, human)
0 (Okazaki fragments)
0 (X-ray Repair Cross Complementing Protein 1)
9007-49-2 (DNA)
0 (XRCC1 protein, human)
EC 3.1.11.- (FEN1 protein, human)
0 (DNA-Binding Proteins)
EC 6.5.1.1 (DNA Ligase ATP)
0 (LIG1 protein, human)
تواريخ الأحداث: Date Created: 20240527 Date Completed: 20240623 Latest Revision: 20240625
رمز التحديث: 20240625
مُعرف محوري في PubMed: PMC11194094
DOI: 10.1093/nar/gkae445
PMID: 38801073
قاعدة البيانات: MEDLINE
الوصف
تدمد:1362-4962
DOI:10.1093/nar/gkae445