ATR safeguards replication forks against APOBEC3B-induced toxic PARP1 trapping DOI Creative Commons
Pedro Ortega, Elodie Bournique, Junyi Li

et al.

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

Published: Nov. 15, 2024

ATR is the master safeguard of genomic integrity during DNA replication. Acute inhibition with inhibitor (ATRi) triggers a surge in origin firing, leading to increased levels single-stranded (ssDNA) that rapidly deplete all available RPA. This leaves ssDNA unprotected and susceptible breakage, phenomenon known as replication catastrophe. However, mechanism by which breaks remains unclear. Here, we reveal APOBEC3B key enzyme targeting at forks, triggering reaction cascade induces fork collapse PARP1 hyperactivation. Mechanistically, demonstrate uracils generated forks are removed UNG2, creating abasic sites subsequently cleaved APE1 endonuclease. Moreover, APE1-mediated cleavage critical enzymatic step for trapping hyperactivation cells, regardless how on DNA. Finally, show APOBEC3B-induced toxic response ATRi drives cell sensitivity inhibition, context synthetic lethality when combined PARP inhibitors. Together, these findings mechanisms cause break catastrophe explain why ATRi-treated cells particularly sensitive

Language: Английский

Endogenous base damage as a driver of genomic instability in homologous recombination-deficient cancers DOI Creative Commons

Lindsey N. Aubuchon,

Priyanka Verma

DNA repair, Journal Year: 2024, Volume and Issue: 141, P. 103736 - 103736

Published: July 31, 2024

Homologous recombination (HR) is a high-fidelity DNA double-strand break (DSB) repair pathway. Both familial and somatic loss of function mutation(s) in various HR genes predispose to variety cancer types, underscoring the importance error-free DSBs human physiology. While environmental sources have been known, more recent studies begun uncover role endogenous base damage leading these breaks. Base intermediates often consist single-strand breaks, which if left unrepaired, can lead as replication fork encounters lesions. This review summarizes how lesions are repaired. We highlight conversion intermediates, particularly those with 5′or 3′ blocked ends, be predominant source genomic instability HR-deficient cancers. also discuss ensuing exploited enhance efficacy Poly (ADP-ribose) polymerase inhibitors (PARPi), that widely used clinics for regimen

Language: Английский

Citations

2
Tolerating DNA damage by repriming: Gap filling in the spotlight DOI Creative Commons
Tiya Jahjah, Jenny Kaur Singh, Vanesa Gottifredi

et al.

DNA repair, Journal Year: 2024, Volume and Issue: 142, P. 103758 - 103758

Published: Aug. 30, 2024

Timely and accurate DNA replication is critical for safeguarding genome integrity ensuring cell viability. Yet, this process challenged by damage blocking the progression of machinery. To counteract fork stalling, evolutionary conserved tolerance (DDT) mechanisms promote bypass movement. One these involves "skipping" through repriming downstream lesion, leaving single-stranded (ssDNA) gaps behind advancing forks (also known as post-replicative gaps). In vertebrates, in damaged leading templates proposed to be mainly promoted primase polymerase PRIMPOL. review, we discuss recent advances towards our understanding physiological pathological conditions activation human models, revealing a regulatory network PRIMPOL activity. Upon PRIMPOL, formed can filled-in DDT translesion synthesis template switching. We novel findings on how are regulated coordinated time gap filling. Finally, defective filling aberrant expansion nucleases underlie cytotoxicity associated with accumulation. Our increasing knowledge mechanism - from formation that targeting last step pathway promising approach exploit anti-cancer therapeutic strategies.

Language: Английский

Citations

2
MRNIP limits ssDNA gaps during replication stress DOI Creative Commons
L Bennett, Ellen G Vernon,

Vithursha Thanendran

et al.

Nucleic Acids Research, Journal Year: 2024, Volume and Issue: 52(14), P. 8320 - 8331

Published: June 25, 2024

Replication repriming by the specialized primase-polymerase PRIMPOL ensures continuity of DNA synthesis during replication stress. activity generates residual post-replicative single-stranded nascent gaps, which are linked with mutagenesis and chemosensitivity in BRCA1/2-deficient models, suppressed fork reversal mediated translocases SMARCAL1 ZRANB3. Here, we report that MRE11 regulator MRNIP limits prevalence MRE11-dependent ssDNA gaps cells is perturbed either treatment PARP inhibitor Olaparib, or depletion MRNIP-deficient sensitive to inhibition accumulate PRIMPOL-dependent damage, supportive a pro-survival role for regulation gap prevalence. In cells, filling driven S-phase UBC13-mediated template switching involving REV1 TLS polymerase Pol-ζ. Our findings represent first modulation dynamics direct regulator.

Language: Английский

Citations

1
The interferon response at the intersection of genome integrity and innate immunity DOI Creative Commons

Filip D. Duzanic,

Lorenza Penengo

DNA repair, Journal Year: 2024, Volume and Issue: 145, P. 103786 - 103786

Published: Nov. 14, 2024

In recent years, numerous reports indicated that, besides pathogen infections, DNA replication stress and defective repair can trigger the innate immune response by introducing a state of viral mimicry, due to cytosolic accumulation self-nucleic acid species, which culminates in activation type I interferon (IFN) pathway. turn, IFN upregulates variety factors mutually implicated immune- genome-related mechanisms, shedding light on unprecedented causality between genome stability immunity. Intriguingly, addition being induced stress, IFN-regulated also promote it, pinpointing signaling as both consequence cause stress. Here, we provide an overview molecular mechanisms evolutionary conserved crosstalk maintenance immunity, highlighting role IFN-stimulated gene 15 (ISG15), appears be at hub this intersection. Moreover, discuss potential significance clinical implications immune-mediated modulation upon infection human diseases such cancer autoinflammatory syndromes. Finally, relevant open questions future directions.

Language: Английский

Citations

1
PARG inhibitor sensitivity correlates with accumulation of single-stranded DNA gaps in preclinical models of ovarian cancer DOI Creative Commons
Ramya Ravindranathan, Ozge Somuncu, Alexandre André Balieiro Anastácio da Costa

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(47)

Published: Nov. 15, 2024

Poly (ADP-ribose) glycohydrolase (PARG) is a dePARylating enzyme which promotes DNA repair by removal of poly (PAR) from PARylated proteins. Loss or inhibition PARG results in replication stress and sensitizes cancer cells to DNA-damaging agents. inhibitors are now undergoing clinical development for patients having tumors with homologous recombination deficiency (HRD), such as germline somatic

Language: Английский

Citations

1
Towards unbiased interpretations of interactive effects in ecotoxicological studies DOI Creative Commons
Antoine Gekière, Guillaume Ghisbain, Maxence Gérard

et al.

Environmental Research, Journal Year: 2024, Volume and Issue: 259, P. 119572 - 119572

Published: July 6, 2024

Ecotoxicological research has increasingly focused on the interactive effects of chemical mixtures biological models, emphasising additive, synergistic, or antagonistic interactions. However, these combination studies often test chemicals at unique concentrations (e.g. x:y), limiting our understanding across full spectrum possible combinations. Evidence from human toxicology suggests that among can vary significantly with total concentration x:y vs. 2x:2y), their ratio x:2y 2x:y), and magnitude tested effect LC

Language: Английский

Citations

1
Recent Advance in Single-Molecule Fluorescent Biosensors for Tumor Biomarker Detection DOI Creative Commons
Jie Zhang, Jiawen Liu,

Lixue Qiao

et al.

Biosensors, Journal Year: 2024, Volume and Issue: 14(11), P. 540 - 540

Published: Nov. 7, 2024

The construction of biosensors for specific, sensitive, and rapid detection tumor biomarkers significantly contributes to biomedical research early cancer diagnosis. However, conventional assays often involve large sample consumption poor sensitivity, limiting their further application in real samples. In recent years, single-molecule biosensing has emerged as a robust tool detecting characterizing due its unique advantages including simplicity, low consumption, ultra-high assay time. This review summarizes the advances measurement various biomarkers, DNAs, DNA modifications, RNAs, enzymes. We give comprehensive about working principles practical applications these biosensors. Additionally, we discuss challenges limitations current biosensors, highlight future directions.

Language: Английский

Citations

1
ATR safeguards replication forks against APOBEC3B-induced toxic PARP1 trapping DOI Creative Commons
Pedro Ortega, Elodie Bournique, Junyi Li

et al.

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

Published: Nov. 15, 2024

ATR is the master safeguard of genomic integrity during DNA replication. Acute inhibition with inhibitor (ATRi) triggers a surge in origin firing, leading to increased levels single-stranded (ssDNA) that rapidly deplete all available RPA. This leaves ssDNA unprotected and susceptible breakage, phenomenon known as replication catastrophe. However, mechanism by which breaks remains unclear. Here, we reveal APOBEC3B key enzyme targeting at forks, triggering reaction cascade induces fork collapse PARP1 hyperactivation. Mechanistically, demonstrate uracils generated forks are removed UNG2, creating abasic sites subsequently cleaved APE1 endonuclease. Moreover, APE1-mediated cleavage critical enzymatic step for trapping hyperactivation cells, regardless how on DNA. Finally, show APOBEC3B-induced toxic response ATRi drives cell sensitivity inhibition, context synthetic lethality when combined PARP inhibitors. Together, these findings mechanisms cause break catastrophe explain why ATRi-treated cells particularly sensitive

Language: Английский

Citations

0