The human Shu complex promotes RAD51 activity by modulating RPA dynamics on ssDNA DOI Creative Commons
Sarah R Hengel, Katherine G. Oppenheimer, Chelsea M. Smith

и другие.

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Авг. 21, 2024

Templated DNA repair that occurs during homologous recombination and replication stress relies on RAD51. RAD51 activity is positively regulated by BRCA2 the paralogs. The Shu complex a paralog-containing consisting of SWSAP1, SWS1, SPIDR. We demonstrate SWSAP1-SWS1 binds RAD51, maintains filament stability, enables strand exchange. Using single-molecule confocal fluorescence microscopy combined with optical tweezers, we show decorates filaments proficient for recombination. also find enhances RPA diffusion ssDNA. Importantly, human sgSWSAP1 sgSWS1 knockout cells are sensitive to pharmacological inhibition PARP APE1. Lastly, identify cancer variants in SWSAP1 alter formation. Together, stimulates RAD51-dependent high-fidelity may be an important new therapeutic target. promotes regulating Here authors reveal proteins, SWSAP1-SWS1, decorate ssDNA facilitate its exchange reaction stimulating knockouts Olaparib sensitive.

Язык: Английский

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

Carly A. Sciandra

и другие.

NAR Cancer, Год журнала: 2023, Номер 5(1)

Опубликована: Янв. 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.

Язык: Английский

Процитировано

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

и другие.

Molecular Cell, Год журнала: 2024, Номер unknown

Опубликована: Янв. 1, 2024

Язык: Английский

Процитировано

31
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
Dynamic de novo heterochromatin assembly and disassembly at replication forks ensures fork stability DOI Creative Commons
Vincent Gaggioli, Calvin Shun Yu Lo, Nazaret Reverón-Gómez

и другие.

Nature Cell Biology, Год журнала: 2023, Номер 25(7), С. 1017 - 1032

Опубликована: Июль 1, 2023

Chromatin is dynamically reorganized when DNA replication forks are challenged. However, the process of epigenetic reorganization and its implication for fork stability poorly understood. Here we discover a checkpoint-regulated cascade chromatin signalling that activates histone methyltransferase EHMT2/G9a to catalyse heterochromatin assembly at stressed forks. Using biochemical single molecule fibre approaches, show G9a together with SUV39h1 induces compaction by accumulating repressive modifications, H3K9me1/me2/me3, in vicinity This closed conformation also favoured G9a-dependent exclusion H3K9-demethylase JMJD1A/KDM3A, which facilitates disassembly upon restart. Untimely from KDM3A enables PRIMPOL access, triggering single-stranded gap formation sensitizing cells towards chemotherapeutic drugs. These findings may help explaining chemotherapy resistance poor prognosis observed patients cancer displaying elevated levels G9a/H3K9me3.

Язык: Английский

Процитировано

30
USP1-dependent nucleolytic expansion of PRIMPOL-generated nascent DNA strand discontinuities during replication stress DOI Creative Commons
Alexandra Nusawardhana,

Lindsey M Pale,

Claudia M. Nicolae

и другие.

Nucleic Acids Research, Год журнала: 2024, Номер 52(5), С. 2340 - 2354

Опубликована: Янв. 5, 2024

DNA replication stress-induced fork arrest represents a significant threat to genomic integrity. One major mechanism of restart involves repriming downstream the arrested by PRIMPOL, leaving behind single-stranded (ssDNA) gap. Accumulation nascent strand ssDNA gaps has emerged as possible determinant cellular hypersensitivity genotoxic agents in certain genetic backgrounds such BRCA deficiency, but how are converted into cytotoxic structures is still unclear. Here, we investigate processing PRIMPOL-dependent upon stress induced hydroxyurea and cisplatin. We show that generated PRIMPOL-overexpressing cells expanded 3'-5' direction MRE11 exonuclease, 5'-3' EXO1 exonuclease. This bidirectional exonucleolytic gap expansion ultimately promotes their conversion DSBs. moreover identify de-ubiquitinating enzyme USP1 critical regulator PRIMPOL-generated gaps. accumulation during S-phase, nucleases. activity linked its role PCNA, suggesting PCNA ubiquitination prevents replication. Finally, depletion suppresses DSB formation cells, highlighting an unexpected for promoting instability under these conditions.

Язык: Английский

Процитировано

13
BRCAness, DNA gaps, and gain and loss of PARP inhibitor–induced synthetic lethality DOI Creative Commons
Xin Li, Lee Zou

Journal of Clinical Investigation, Год журнала: 2024, Номер 134(14)

Опубликована: Июль 14, 2024

Mutations in the tumor-suppressor genes BRCA1 and BRCA2 resulting BRCA1/2 deficiency are frequently identified breast, ovarian, prostate, pancreatic, other cancers. Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) selectively kill BRCA1/2-deficient cancer cells by inducing synthetic lethality, providing an effective biomarker-guided strategy for targeted therapy. However, a substantial fraction of patients carrying mutations do not respond to PARPis, most develop resistance PARPis over time, highlighting major obstacle PARPi therapy clinic. Recent studies have revealed that changes specific functional defects cells, particularly their suppressing protecting single-stranded DNA gaps, contribute gain or loss PARPi-induced lethality. These findings only shed light on mechanism action but also lead revised models explain how BRCA-deficient cells. Furthermore, new mechanistic principles sensitivity emerged from these studies, generating potentially useful guidelines predicting response design therapies overcoming resistance. In this Review, we will discuss recent put them context with classic views aiming stimulate development therapeutic strategies overcome improve

Язык: Английский

Процитировано

13
FANCJ promotes PARP1 activity during DNA replication that is essential in BRCA1 deficient cells DOI Creative Commons
Ke Cong, Nathan J. MacGilvary, Silviana Lee

и другие.

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Март 23, 2024

The effectiveness of poly (ADP-ribose) polymerase inhibitors (PARPi) in creating single-stranded DNA gaps and inducing sensitivity requires the FANCJ helicase. Yet, how relates to PARP1 inhibition or trapping, which contribute PARPi toxicity, remains unclear. Here, we find hinges on S-phase activity, is reduced deficient cells as G-quadruplexes sequester MSH2. Additionally, loss FANCJ-MLH1 interaction diminishes activity; however, depleting MSH2 reinstates gaps. Indicating sequestered trapped are distinct, increases resistance susceptible trapping. However, with BRCA1 deficiency, mirrors inhibition, detrimental commonality being activity. These insights underline crucial role activity during replication emphasize importance understanding drug mechanisms for enhancing therapeutic response.

Язык: Английский

Процитировано

12
Targeting BRCA1-deficient PARP inhibitor-resistant cells with nickases reveals nick resection as a cancer vulnerability DOI

Jenna Whalen,

Jillian Earley,

Christi Wisniewski

и другие.

Nature Cancer, Год журнала: 2025, Номер unknown

Опубликована: Янв. 21, 2025

Язык: Английский

Процитировано

1
The Landscape of PARP Inhibitors in Solid Cancers DOI Open Access

Marta Muzzana,

Massimo Broggini, Giovanna Damia

и другие.

OncoTargets and Therapy, Год журнала: 2025, Номер Volume 18, С. 297 - 317

Опубликована: Март 1, 2025

PARP inhibitors are a class of agents that have shown significant preclinical activity in models defective homologous recombination (HR). The identification synthetic lethality between HR defects and inhibition led to several clinical trials tumors with known (initially mutations BRCA1/2 genes subsequently other involved HR). These studies demonstrated responses breast ovarian cancers, which proportion patients defects. Since the approval first inhibitor (PARPi), olaparib, been developed, expanding armamentarium available clinicians this setting. positive results obtained cancer expanded use PARPi solid defects, including prostate pancreatic these identified. now also for subset This review summarizes their potential when combined agents, immune checkpoint likely further increase survival still needs dramatic improvement.

Язык: Английский

Процитировано

1