ArticleCell reports2024
Poly(ADP-ribosyl)ation of TIMELESS limits DNA replication stress and promotes stalled fork protection.
Article in Cell reports, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 21 citations in OpenAlex.
- FET proteins and PARylation-dependent condensates promote replication fork reversal and genome stability.Nature communications · 2026Article
- Two fork protection complexes at the replication fork play distinct roles in fork progression and stress response.Research square · 2026Article
- A Large-Scale Method to Measure the Stoichiometries of Protein Poly-ADP-Ribosylation.ACS chemical biology · 2026Article
- Decoding replication stress responses through post-translational modifications.Nature chemical biology · 2025Review
- Hyperthermia-induced BRCA2 reduction potentiates PARPi sensitivity in BRCA2-proficient ovarian carcinoma.Discover oncology · 2025Article
- TIPIN coordinates ATM-dependent checkpoint and NF-κB signaling to counteract DNA replication damage from topoisomerase inhibition.Communications biology · 2025Article
- Loss of DNA replication fork protection by TIMELESS degradation supports oncogene-induced senescence.Biochemical and biophysical research communications · 2025Article
- Article
- The DNA-PKcs/JNK/p53 pathway underlies changes in cell fate decision toward death during DNA replication catastrophe.Nucleic acids research · 2025Article
- Identification of modulators of the ALT pathway through a native FISH-based optical screen.Cell reports · 2025Article
- Circadian genes and non-coding RNAs: interactions and implications in cancer.Animal cells and systems · 2025Review
- Identification of Novel Modulators of the ALT Pathway Through a Native FISH-Based Optical Screen.bioRxiv : the preprint server for biology · 2024Article
- Intrinsic PARG inhibitor sensitivity is mimicked byNAR cancer · 2024Article
- PARP1-driven repair of topoisomerase IIIα DNA-protein crosslinks by FEN1.Cell reports · 2024Article
- Synthetic lethality by PARP inhibitors: new mechanism uncovered based on unresolved transcription-replication conflicts.Signal transduction and targeted therapy · 2024Article
- The TIMELESS and PARP1 interaction suppresses replication-associated DNA gap accumulation.Nucleic acids research · 2024Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Poly(ADP-ribosyl)ation (PARylation), catalyzed mainly by poly(ADP-ribose) polymerase (PARP)1, is a key posttranslational modification involved in DNA replication and repair. Here, we report that TIMELESS (TIM), an essential scaffold of the replisome, is PARylated, which is linked to its proteolysis. TIM PARylation requires recognition of auto-modified PARP1 via two poly(ADP-ribose)-binding motifs, which primes TIM for proteasome-dependent degradation. Cells expressing the PARylation-refractory TIM mutant or under PARP inhibition accumulate TIM at DNA replication forks, causing replication stress and hyper-resection of stalled forks. Mechanistically, aberrant engagement of TIM with the replicative helicase impedes RAD51 loading and protection of reversed forks. Accordingly, defective TIM degradation hypersensitizes BRCA2-deficient cells to replication damage. Our study defines TIM as a substrate of PARP1 and elucidates how the control of replisome remodeling by PARylation is linked to stalled fork protection. Therefore, we propose a mechanism of PARP inhibition that impinges on the DNA replication fork instability caused by defective TIM turnover.
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