Intrinsic PARG inhibitor sensitivity is mimicked by TIMELESS haploinsufficiency and rescued by nucleoside supplementation DOI Creative Commons
Camilla Coulson‐Gilmer, Samantha Littler, Bethany M. Barnes

et al.

NAR Cancer, Journal Year: 2024, Volume and Issue: 6(3)

Published: July 9, 2024

A subset of cancer cells are intrinsically sensitive to inhibitors targeting PARG, the poly(ADP-ribose) glycohydrolase that degrades PAR chains. Sensitivity is accompanied by persistent DNA replication stress, and can be induced inhibition

Language: Английский

The TIMELESS and PARP1 interaction suppresses replication-associated DNA gap accumulation DOI Creative Commons
Joanne Saldanha, Julie Rageul,

Jinal A Patel

et al.

Nucleic Acids Research, Journal Year: 2024, Volume and Issue: 52(11), P. 6424 - 6440

Published: May 27, 2024

Abstract TIMELESS (TIM) in the fork protection complex acts as a scaffold of replisome to prevent its uncoupling and ensure efficient DNA replication progression. Nevertheless, underlying basis for coordinating leading lagging strand synthesis limit single-stranded (ssDNA) exposure remains elusive. Here, we demonstrate that acute degradation TIM at ongoing forks induces accumulation ssDNA gaps stemming from defective Okazaki fragment (OF) processing. Cells devoid fail support poly(ADP-ribosyl)ation necessary backing up canonical OF processing mechanism mediated by LIG1 FEN1. Consequently, recruitment XRCC1, known effector PARP1-dependent single-strand break repair, post-replicative behind is impaired. Physical disruption TIM–PARP1 phenocopies rapid loss TIM, indicating interaction critical activation this compensatory pathway. Accordingly, combined deficiency FEN1 leads synergistic damage cytotoxicity. We propose essential engagement PARP1 coordinate with Our study identifies synthetic lethal target enzymes can be exploited cancer therapy.

Language: Английский

Citations

9
Synthetic lethality by PARP inhibitors: new mechanism uncovered based on unresolved transcription-replication conflicts DOI Creative Commons
Marina Kolesnichenko, Claus Scheidereit

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: July 29, 2024

Language: Английский

Citations

4
Circadian genes and non-coding RNAs: interactions and implications in cancer DOI Creative Commons
Gyesoon Yoon, Jungwook Roh,

Wonyi Jang

et al.

Animal Cells and Systems, Journal Year: 2025, Volume and Issue: 29(1), P. 135 - 148

Published: Feb. 11, 2025

Circadian rhythms are 24-hour cycles in various biological processes, such as sleep, wake, and hormone secretion, controlled by an internal clock. Disruption of circadian has been related to human diseases. Abnormal expression rhythm-related genes, CLOCK, BMAL1, PER1, PER2, CRY1, CRY2, RORα, NPAS2, REV-ERBα TIMELESS also reported be associated with cancer. NPAS2 cancer development. In contrast, RORα inhibit development progression. Furthermore, studies suggest that genes can regulated ncRNAs miRNAs, lncRNAs circRNAs dysregulation these contributes Here, we summarize the mechanisms whereby ncRNA leads abnormal several cancers gene-associated regulatory contribute resistance chemo – radiotherapy. This review provides insights into mechanistic involvements network

Language: Английский

Citations

0
A large-scale method to measure the absolute stoichiometries of protein Poly-ADP-Ribosylation DOI Creative Commons
Peng Li, Yajie Zhang, Yonghao Yu

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 27, 2025

Poly-ADP-ribosylation (PARylation) is a reversible posttranslational modification that occurs in higher eukaryotes. While thousands of PARylated substrates have been identified, the specific biological functions most proteins remain elusive. PARylation stoichiometry critical parameter to assess potential protein. Here, we developed large-scale strategy measure absolute stoichiometries protein PARylation. By integrating mild cell lysis, boronate enrichment and carefully designed titration experiments, were able determine for total 235 proteins. This approach enables capture all events on various amino acid acceptors. We revealed occupancy spans over three orders magnitude. However, occur at low stoichiometric values (median 0.578%). Notably, observed high (>1%) predominantly targets involved transcription regulation chromatin remodeling. Thus, our study provides systems-scale, quantitative view under genotoxic conditions, which serves as invaluable resources future functional studies this important modification.

Language: Английский

Citations

0
PARP inhibitors in ovarian cancer: mechanisms of resistance and implications to therapy DOI Creative Commons

Sanat Kulkarni,

N. Seneviratne,

Çağla Tosun

et al.

DNA repair, Journal Year: 2025, Volume and Issue: unknown, P. 103830 - 103830

Published: April 1, 2025

Advanced epithelial ovarian cancer of the high-grade serous subtype (HGSOC) remains a significant clinical challenge due to development resistance current platinum-based chemotherapies. PARP1/2 inhibitors (PARPi) exploit well-characterised homologous recombination repair deficiency (HRD) in HGSOC and offer an effective targeted approach treatment. Several trials demonstrated that PARPi (olaparib, rucaparib, niraparib) significantly improved progression-free survival (PFS) recurrent maintenance setting. However, 40-70 % patients develop Resistance presenting ongoing clinic. Therefore, there is unmet need for novel therapies biomarkers identify intrinsic or acquired cancer. Understanding mechanisms crucial identifying molecular vulnerabilities, developing patient stratification guiding treatment decisions. Here, we summarise landscape associated with such as restored functionality, replication fork stability alterations PARP1 PARP2 DNA damage response. We highlight role circulating tumour (ctDNA) its potential 'real-time' Moreover, explore other innovative strategies aimed at overcoming specific mechanisms, including inhibition ATR, WEE1 POLQ. also examine rechallenge resistance.

Language: Английский

Citations

0
PARP1-driven repair of topoisomerase IIIα DNA-protein crosslinks by FEN1 DOI Creative Commons
Liton Kumar Saha, Yilun Sun,

Sourav Saha

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(8), P. 114522 - 114522

Published: July 18, 2024

Persistent DNA-protein crosslinks formed by human topoisomerase IIIα (TOP3A-DPCs) interfere with DNA metabolism and lead to genome damage cell death. Recently, we demonstrated that such abortive TOP3A-DPCs are ubiquitylated proteolyzed Spartan (SPRTN). Here, identify transient poly(ADP-ribosylation) (PARylation) in addition ubiquitylation as a signaling mechanism for TOP3A-DPC repair provide evidence poly(ADP-ribose) polymerase 1 (PARP1) drives the of recruiting flap endonuclease (FEN1) TOP3A-DPCs. We find blocking PARylation attenuates interaction FEN1 TOP3A accumulate cells compromised PARP1 activity FEN1-deficient cells. also show suppresses inhibiting ubiquitin-activating enzyme E1 (UBE1) increases TOP3A-DPCs, consistent serving mediated SPRTN TDP2. propose two concerted pathways TOP3A-DPCs: PARylation-driven excision ubiquitylation-driven SPRTN-TDP2 excision.

Language: Английский

Citations

2
Identification of Novel Modulators of the ALT Pathway Through a Native FISH-Based Optical Screen DOI Creative Commons
Benura Azeroglu, Shikhar Khurana,

Shih-Chun Wang

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 15, 2024

A significant portion of human cancers utilize a recombination-based pathway, Alternative Lengthening Telomeres (ALT), to extend telomeres. To gain further insights into this we developed high-throughput imaging-based screen named TAILS (Telomeric ALT

Language: Английский

Citations

1
USP37 protects mammalian cells during DNA replication stress by counteracting CUL2-LRR1 and TRAIP DOI Creative Commons
Fabrizio Villa, Johanna Ainsworth, Karim Labib

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 3, 2024

Summary The USP37 deubiquitylase is important for mammalian cells to survive DNA replication stress but the underlying mechanisms are unknown. Here we demonstrate that binds CDC45-MCM-GINS (CMG) helicase, which forms stable core of replisome and regulated by ubiquitylation. Pleckstrin-Homology Domain CDC45 structure-guided mutations displace from CMG sufficient phenocopy loss catalytic activity. Importantly, counteracts helicase ubiquitylation CUL2 LRR1 ligase, induces disassembly during termination. We show depletion suppresses sensitivity Usp37 mutants synthesis defects ATR checkpoint kinase inhibitors. In contrast, mutation TRAIP ubiquitin ligase specifically topological chromosome replication. propose evolved reverse untimely action two ligases regulate in metazoa.

Language: Английский

Citations

0
Identification of modulators of the ALT pathway through a native FISH-based optical screen DOI Creative Commons
Benura Azeroglu, Shikhar Khurana,

Shih-Chun Wang

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 44(1), P. 115114 - 115114

Published: Dec. 26, 2024

Language: Английский

Citations

0
Intrinsic PARG inhibitor sensitivity is mimicked by TIMELESS haploinsufficiency and rescued by nucleoside supplementation DOI Creative Commons
Camilla Coulson‐Gilmer, Samantha Littler, Bethany M. Barnes

et al.

NAR Cancer, Journal Year: 2024, Volume and Issue: 6(3)

Published: July 9, 2024

A subset of cancer cells are intrinsically sensitive to inhibitors targeting PARG, the poly(ADP-ribose) glycohydrolase that degrades PAR chains. Sensitivity is accompanied by persistent DNA replication stress, and can be induced inhibition

Language: Английский

Citations

0