ATR protects ongoing and newly assembled DNA replication forks through distinct mechanisms DOI Creative Commons

Wendy Leung,

Antoine Simoneau, Sneha Saxena

et al.

Cell Reports, Journal Year: 2023, Volume and Issue: 42(7), P. 112792 - 112792

Published: July 1, 2023

The ATR kinase safeguards genomic integrity during S phase, but how protects DNA replication forks remains incompletely understood. Here, we combine four distinct assays to analyze functions at ongoing and newly assembled upon inhibition by hydroxyurea. At forks, inhibitor (ATRi) increases MRE11- EXO1-mediated nascent degradation from PrimPol-generated, single-stranded (ssDNA) gaps. ATRi also exposes template ssDNA through fork uncoupling degradation. Electron microscopy reveals that reduces reversed increasing gap-dependent new triggers CtIP-initiated EXO1, exposing ssDNA. Upon PARP inhibition, preferentially exacerbates in BRCA1/2-deficient cells disrupts the restored gap protection BRCA1-deficient, PARP-inhibitor-resistant cells. Thus, mechanisms, providing an extended view of ATR's stabilizing forks.

Language: Английский

Hallmarks of DNA replication stress DOI Creative Commons
Sneha Saxena, Lee Zou

Molecular Cell, Journal Year: 2022, Volume and Issue: 82(12), P. 2298 - 2314

Published: June 1, 2022

Language: Английский

Citations

221
DNA repair defects in cancer and therapeutic opportunities DOI Open Access

Jessica L. Hopkins,

Li Lan, Lee Zou

et al.

Genes & Development, Journal Year: 2022, Volume and Issue: 36(5-6), P. 278 - 293

Published: March 1, 2022

DNA repair and damage signaling pathways are critical for the maintenance of genomic stability. Defects contribute to tumorigenesis, but also render cancer cells vulnerable reliant on remaining activities. Here, we review major classes defects in cancer, instability that they give rise to, therapeutic strategies exploit resulting vulnerabilities. Furthermore, discuss impacts both targeted therapy immunotherapy, highlight emerging principles targeting therapy.

Language: Английский

Citations

120
PARP inhibition impedes the maturation of nascent DNA strands during DNA replication DOI Creative Commons
Alina Vaitsiankova, Kamila Burdová, Margarita Sobol

et al.

Nature Structural & Molecular Biology, Journal Year: 2022, Volume and Issue: 29(4), P. 329 - 338

Published: March 24, 2022

Abstract Poly(ADP-ribose) polymerase 1 (PARP1) is implicated in the detection and processing of unligated Okazaki fragments other DNA replication intermediates, highlighting such structures as potential sources genome breakage induced by PARP inhibition. Here, we show that PARP1 activity greatly elevated chicken human S phase cells which FEN1 nuclease genetically deleted highest behind forks. inhibitor reduces integrity nascent strands both wild-type during replication, does so − / to an even greater extent can be detected postreplicative single-strand nicks or gaps. Collectively, these data inhibitors impede maturation implicate strand discontinuities cytotoxicity compounds.

Language: Английский

Citations

111
Leveraging the replication stress response to optimize cancer therapy DOI
Emily Cybulla, Alessandro Vindigni

Nature reviews. Cancer, Journal Year: 2022, Volume and Issue: 23(1), P. 6 - 24

Published: Nov. 2, 2022

Language: Английский

Citations

69
Roles of trans-lesion synthesis (TLS) DNA polymerases in tumorigenesis and cancer therapy DOI Creative Commons
Jay Ramanlal Anand, Lilly Chiou,

Carly A. Sciandra

et al.

NAR Cancer, Journal Year: 2023, Volume and Issue: 5(1)

Published: Jan. 11, 2023

Abstract DNA damage tolerance and mutagenesis are hallmarks enabling characteristics of neoplastic cells that drive tumorigenesis allow cancer to resist therapy. The ‘Y-family’ trans-lesion synthesis (TLS) polymerases enable replicate damaged genomes, thereby conferring tolerance. Moreover, Y-family inherently error-prone cause mutations. Therefore, TLS potential mediators important tumorigenic phenotypes. skin cancer-propensity syndrome xeroderma pigmentosum-variant (XPV) results from defects in the Polymerase Pol eta (Polη) compensatory deployment alternative inappropriate polymerases. However, extent which dysregulated contributes underlying etiology other human cancers is unclear. Here we consider broad impact on We survey ways pathologically altered cancer. summarize evidence shape review studies implicating as a driver carcinogenesis. Because many treatment regimens comprise DNA-damaging agents, pharmacological inhibition an attractive strategy for sensitizing tumors genotoxic therapies. discuss tractability pathway recent progress development inhibitors therapeutic purposes.

Language: Английский

Citations

44
BRCA2 promotes genomic integrity and therapy resistance primarily through its role in homology-directed repair DOI Creative Commons
Pei Xin Lim,

Mahdia Zaman,

Weiran Feng

et al.

Molecular Cell, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Language: Английский

Citations

31
APOBEC3A induces DNA gaps through PRIMPOL and confers gap-associated therapeutic vulnerability DOI Creative Commons
Ajinkya S. Kawale, Xiaojuan Ran, Parasvi S. Patel

et al.

Science Advances, Journal Year: 2024, Volume and Issue: 10(3)

Published: Jan. 19, 2024

Mutation signatures associated with apolipoprotein B mRNA editing catalytic polypeptide-like 3A/B (APOBEC3A/B) cytidine deaminases are prevalent across cancers, implying their roles as mutagenic drivers during tumorigenesis and tumor evolution. APOBEC3A (A3A) expression induces DNA replication stress increases the cellular dependency on ataxia telangiectasia Rad3-related (ATR) kinase for survival. Nonetheless, how A3A remains unclear. We show that without slowing forks. find single-stranded (ssDNA) gaps through PrimPol-mediated repriming. A3A-induced ssDNA repaired by multiple pathways involving ATR, RAD51, translesion synthesis. Both ATR inhibition trapping of poly(ADP-ribose) polymerase (PARP) PARP inhibitor impair repair gaps, preferentially killing A3A-expressing cells. When used in combination, inhibitors selectively kill cells synergistically a manner dependent PrimPol-generated gaps. Thus, arises from which confer therapeutic vulnerability to gap-targeted inhibitors.

Language: Английский

Citations

17
Exploiting replication gaps for cancer therapy DOI Creative Commons
Ke Cong, Sharon B. Cantor

Molecular Cell, Journal Year: 2022, Volume and Issue: 82(13), P. 2363 - 2369

Published: May 13, 2022

Language: Английский

Citations

67
POLθ prevents MRE11-NBS1-CtIP-dependent fork breakage in the absence of BRCA2/RAD51 by filling lagging-strand gaps DOI Creative Commons

Anjali Mann,

Miguel Angel Ramírez-Otero, Anna De Antoni

et al.

Molecular Cell, Journal Year: 2022, Volume and Issue: 82(22), P. 4218 - 4231.e8

Published: Nov. 1, 2022

POLθ promotes repair of DNA double-strand breaks (DSBs) resulting from collapsed forks in homologous recombination (HR) defective tumors. Inactivation results synthetic lethality with the loss HR genes BRCA1/2, which induces under-replicated accumulation. However, it is unclear whether POLθ-dependent replication prevents HR-deficiency-associated lethality. Here, we isolated Xenopus laevis and showed that processes stalled Okazaki fragments, directly visualized by electron microscopy, thereby suppressing ssDNA gaps accumulating on lagging strands absence RAD51 preventing fork reversal. Inhibition polymerase activity leaves unprotected, enabling their cleavage MRE11-NBS1-CtIP endonuclease, produces broken asymmetric single-ended DSBs, hampering BRCA2-defective cell survival. These reveal a genome protection function rupture highlight possible resistance mechanisms to inhibitors.

Language: Английский

Citations

57
POLθ processes ssDNA gaps and promotes replication fork progression in BRCA1-deficient cells DOI Creative Commons
Anna Schrempf,

Sara Bernardo,

Emili A. Arasa Verge

et al.

Cell Reports, Journal Year: 2022, Volume and Issue: 41(9), P. 111716 - 111716

Published: Nov. 1, 2022

Polymerase theta (POLθ) is an error-prone DNA polymerase whose loss synthetically lethal in cancer cells bearing breast susceptibility proteins 1 and 2 (BRCA1/2) mutations. To investigate the basis of this genetic interaction, we utilized a small-molecule inhibitor targeting POLθ domain. We found that processes single-stranded (ssDNA) gaps emerge absence BRCA1, thus promoting unperturbed replication fork progression survival BRCA1 mutant cells. A genome-scale CRISPR-Cas9 knockout screen uncovered suppressors functional interaction between including NBN, component MRN complex, cell-cycle regulators such as CDK6. While complex nucleolytically ssDNA gaps, CDK6 promotes progression, thereby exacerbating stress, feature BRCA1-deficient lack activity. Thus, gap formation, modulated by activity, underlies synthetic lethality important insight for clinical trials with inhibitors.

Language: Английский

Citations

47