Unrepaired base excision repair intermediates in template DNA strands trigger replication fork collapse and PARP inhibitor sensitivity DOI Creative Commons
Almudena Serrano-Benítez, Sophie E. Wells, Lylah Drummond‐Clarke

и другие.

The EMBO Journal, Год журнала: 2023, Номер 42(18)

Опубликована: Июль 26, 2023

Abstract DNA single‐strand breaks (SSBs) disrupt replication and induce chromosome breakage. However, whether SSBs breakage when present behind forks or ahead of is unclear. To address this question, we exploited an exquisite sensitivity SSB repair‐defective human cells lacking PARP activity XRCC1 to the thymidine analogue 5‐chloro‐2′‐deoxyuridine (CldU). We show that incubation with CldU in these results breakage, sister chromatid exchange, cytotoxicity by a mechanism depends on S phase uracil glycosylase (UNG). Importantly, incorporation one cell cycle cytotoxic only during following cycle, it template DNA. In agreement this, while UNG induces both nascent strands forks, latter trigger fork collapse Finally, BRCA‐defective are hypersensitive CldU, either alone and/or combination inhibitor, suggesting may have clinical utility.

Язык: Английский

Targeting DNA damage response pathways in cancer DOI
Florian J. Groelly,

Matthew Fawkes,

Rebecca A. Dagg

и другие.

Nature reviews. Cancer, Год журнала: 2022, Номер 23(2), С. 78 - 94

Опубликована: Дек. 5, 2022

Язык: Английский

Процитировано

433
Leveraging the replication stress response to optimize cancer therapy DOI
Emily Cybulla, Alessandro Vindigni

Nature reviews. Cancer, Год журнала: 2022, Номер 23(1), С. 6 - 24

Опубликована: Ноя. 2, 2022

Язык: Английский

Процитировано

69
ADP-ribosylation from molecular mechanisms to therapeutic implications DOI Creative Commons
Marcin J. Suskiewicz, Evgeniia Prokhorova, J.G.M. Rack

и другие.

Cell, Год журнала: 2023, Номер 186(21), С. 4475 - 4495

Опубликована: Окт. 1, 2023

ADP-ribosylation is a ubiquitous modification of biomolecules, including proteins and nucleic acids, that regulates various cellular functions in all kingdoms life. The recent emergence new technologies to study has reshaped our understanding the molecular mechanisms govern establishment, removal, recognition this modification, as well its impact on organismal function. These advances have also revealed intricate involvement human physiology pathology enormous potential their manipulation holds for therapy. In review, we present state-of-the-art findings covering work structural biology, biochemistry, cell clinical aspects ADP-ribosylation.

Язык: Английский

Процитировано

68
The DNA Damage Response and Inflammation in Cancer DOI
Vanessa Klapp, Beatriz Álvarez-Abril, Giuseppe Leuzzi

и другие.

Cancer Discovery, Год журнала: 2023, Номер 13(7), С. 1521 - 1545

Опубликована: Апрель 7, 2023

Genomic stability in normal cells is crucial to avoid oncogenesis. Accordingly, multiple components of the DNA damage response (DDR) operate as bona fide tumor suppressor proteins by preserving genomic stability, eliciting demise with unrepairable lesions, and engaging cell-extrinsic oncosuppression via immunosurveillance. That said, DDR sig-naling can also favor progression resistance therapy. Indeed, signaling cancer has been consistently linked inhibition tumor-targeting immune responses. Here, we discuss complex interactions between inflammation context oncogenesis, progression, Accumulating preclinical clinical evidence indicates that intimately connected emission immunomodulatory signals malignant cells, part a program preserve organismal homeostasis. DDR-driven inflammation, however, have diametrically opposed effects on immunity. Understanding links may unlock novel immunotherapeutic paradigms treat cancer.

Язык: Английский

Процитировано

55
Direct visualization of transcription-replication conflicts reveals post-replicative DNA:RNA hybrids DOI Creative Commons
Henriette Stoy,

Katharina Zwicky,

Danina Kuster

и другие.

Nature Structural & Molecular Biology, Год журнала: 2023, Номер 30(3), С. 348 - 359

Опубликована: Март 1, 2023

Abstract Transcription-replication collisions (TRCs) are crucial determinants of genome instability. R-loops were linked to head-on TRCs and proposed obstruct replication fork progression. The underlying mechanisms, however, remained elusive due the lack direct visualization non-ambiguous research tools. Here, we ascertained stability estrogen-induced on human genome, visualized them directly by electron microscopy (EM), measured R-loop frequency size at single-molecule level. Combining EM immuno-labeling locus-specific in bacteria, observed frequent accumulation DNA:RNA hybrids behind forks. These post-replicative structures slowing reversal across conflict regions distinct from physiological Okazaki fragments. Comet assays nascent DNA revealed a marked delay maturation multiple conditions previously accumulation. Altogether, our findings suggest that TRC-associated interference entails transactions follow initial bypass fork.

Язык: Английский

Процитировано

44
Causes and consequences of DNA single-strand breaks DOI Creative Commons
Keith W. Caldecott

Trends in Biochemical Sciences, Год журнала: 2023, Номер 49(1), С. 68 - 78

Опубликована: Ноя. 30, 2023

DNA single-strand breaks (SSBs) are among the most common lesions arising in human cells, with tens to hundreds of thousands each cell, day. Cells have efficient mechanisms for sensing and repair these ubiquitous lesions, but failure processes rapidly remove SSBs can lead a variety pathogenic outcomes. The threat posed by unrepaired is illustrated existence at least six genetic diseases which SSB (SSBR) defective, all characterised neurodevelopmental and/or neurodegenerative pathology. Here, I review current understanding how arise impact on critical molecular processes, such as replication gene transcription, their links disease.

Язык: Английский

Процитировано

43
BLM helicase unwinds lagging strand substrates to assemble the ALT telomere damage response DOI
Haoyang Jiang, Tianpeng Zhang,

Hardeep Kaur

и другие.

Molecular Cell, Год журнала: 2024, Номер 84(9), С. 1684 - 1698.e9

Опубликована: Апрель 8, 2024

Язык: Английский

Процитировано

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

и другие.

Molecular Cell, Год журнала: 2024, Номер 84(4), С. 659 - 674.e7

Опубликована: Янв. 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

Язык: Английский

Процитировано

15
Exploiting replication gaps for cancer therapy DOI Creative Commons
Ke Cong, Sharon B. Cantor

Molecular Cell, Год журнала: 2022, Номер 82(13), С. 2363 - 2369

Опубликована: Май 13, 2022

Язык: Английский

Процитировано

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

и другие.

Molecular Cell, Год журнала: 2022, Номер 82(22), С. 4218 - 4231.e8

Опубликована: Ноя. 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.

Язык: Английский

Процитировано

57