Freedom to err: The expanding cellular functions of translesion DNA polymerases DOI Creative Commons
Inés Paniagua, Jacqueline J.L. Jacobs

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(20), P. 3608 - 3621

Published: Aug. 24, 2023

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

224
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

121
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

112
POLQ seals post-replicative ssDNA gaps to maintain genome stability in BRCA-deficient cancer cells DOI Creative Commons

Ondrej Beláň,

Marie Sebald,

Marek Adamowicz

et al.

Molecular Cell, Journal Year: 2022, Volume and Issue: 82(24), P. 4664 - 4680.e9

Published: Nov. 30, 2022

POLQ is a key effector of DSB repair by microhomology-mediated end-joining (MMEJ) and overexpressed in many cancers. inhibitors confer synthetic lethality HR Shieldin-deficient cancer cells, which has been proposed to reflect critical dependence on the pathway MMEJ. Whether also operates independent MMEJ remains unexplored. Here, we show that POLQ-deficient cells accumulate post-replicative ssDNA gaps upon BRCA1/2 loss or PARP inhibitor treatment. Biochemically, cooperation between helicase polymerase activities promotes RPA displacement ssDNA-gap fill-in, respectively. capable gap skipping (MMGS), generates deletions during resemble genomic scars prevalent overexpressing Our findings implicate mutagenic sealing, could drive genome evolution whose places dependency for protection cellular viability.

Language: Английский

Citations

84
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

70
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
SMARCAL1 is a dual regulator of innate immune signaling and PD-L1 expression that promotes tumor immune evasion DOI Creative Commons
Giuseppe Leuzzi, Alessandro Vasciaveo, Angelo Taglialatela

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(4), P. 861 - 881.e32

Published: Jan. 31, 2024

Language: Английский

Citations

36
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

18
EXO1 protects BRCA1-deficient cells against toxic DNA lesions DOI Creative Commons
Bert van de Kooij, Anne Schreuder, Raphael Pavani

et al.

Molecular Cell, Journal Year: 2024, Volume and Issue: 84(4), P. 659 - 674.e7

Published: Jan. 23, 2024

Inactivating mutations in the BRCA1 and BRCA2 genes impair DNA double-strand break (DSB) repair by homologous recombination (HR), leading to chromosomal instability cancer. Importantly, BRCA1/2 deficiency also causes therapeutically targetable vulnerabilities. Here, we identify dependency on end resection factor EXO1 as a key vulnerability of BRCA1-deficient cells. generates poly(ADP-ribose)-decorated lesions during S phase that associate with unresolved DSBs genomic but not wild-type or BRCA2-deficient Our data indicate BRCA1/EXO1 double-deficient cells accumulate due impaired single-strand annealing (SSA) top their HR defect. In contrast, retain SSA activity absence hence tolerate loss. Consistent EXO1-mediated SSA, find BRCA1-mutated tumors show elevated expression increased SSA-associated scars compared BRCA1-proficient tumors. Overall, our findings uncover promising therapeutic target for

Language: Английский

Citations

16