DNA damage checkpoint kinases in cancer

Expert Reviews in Molecular Medicine, Journal Year: 2020, Volume and Issue: 22

Published: Jan. 1, 2020

Abstract DNA damage response (DDR) pathway prevents high level endogenous and environmental being replicated passed on to the next generation of cells via an orchestrated integrated network cell cycle checkpoint signalling repair pathways. Depending type damage, where in it occurs different pathways are involved, with ATM-CHK2-p53 controlling G1 or ATR-CHK1-Wee1 S G2/M checkpoints. Loss control is common cancer through TP53, ATM mutations, Rb loss cyclin E overexpression, providing a stronger rationale for targeting S/G2 This review will focus ATM-CHK2-p53-p21 ATR-CHK1-WEE1 ongoing efforts target these patient benefit.

Language: Английский

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Hallmarks of DNA replication stress

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

Published: June 1, 2022

Language: Английский

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53BP1: a DSB escort

Genes & Development, Journal Year: 2020, Volume and Issue: 34(1-2), P. 7 - 23

Published: Jan. 1, 2020

53BP1 is an enigmatic DNA damage response factor that gained prominence because it determines the efficacy of PARP1 inhibitory drugs (PARPi) in BRCA1-deficient cancers. Recent studies have elevated from its modest status (yet another) to master regulator double-strand break (DSB) repair pathway choice. Our review literature suggests alternative view. We propose has evolved avoid mutagenic outcomes and does so by controlling processing ends dynamics DSBs. The consequences deficiency, such as diminished PARPi cells altered damaged telomeres, can be explained this viewpoint. further some fidelity functions coevolved with class switch recombination (CSR) immune system. speculate that, rather than being deterministic DSB choice, a escort guards against illegitimate potentially tumorigenic recombination.

Language: Английский

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PRIMPOL-Mediated Adaptive Response Suppresses Replication Fork Reversal in BRCA-Deficient Cells

Molecular Cell, Journal Year: 2019, Volume and Issue: 77(3), P. 461 - 474.e9

Published: Oct. 30, 2019

Acute treatment with replication-stalling chemotherapeutics causes reversal of replication forks. BRCA proteins protect reversed forks from nucleolytic degradation, and their loss leads to chemosensitivity. Here, we show that fork degradation is no longer detectable in BRCA1-deficient cancer cells exposed multiple cisplatin doses, mimicking a clinical regimen. This effect depends on increased expression chromatin loading PRIMPOL regulated by ATR activity. Electron microscopy single-molecule DNA fiber analyses reveal rescues reinitiating synthesis past lesions. repriming accumulation ssDNA gaps while suppressing reversal. We propose adapt repeated doses activating under conditions would otherwise promote pathological degradation. generalizable other impaired (e.g., SMARCAL1 or PARP inhibition) suggests new strategy modulate chemosensitivity targeting the pathway.

Language: Английский

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The Colibactin Genotoxin Generates DNA Interstrand Cross-Links in Infected Cells

mBio, Journal Year: 2018, Volume and Issue: 9(2)

Published: March 19, 2018

ABSTRACT Colibactins are hybrid polyketide-nonribosomal peptides produced by Escherichia coli , Klebsiella pneumoniae and other Enterobacteriaceae harboring the pks genomic island. These genotoxic metabolites -encoded peptide-polyketide synthases as inactive prodrugs called precolibactins, which then converted to colibactins deacylation for DNA-damaging effects. bona fide virulence factors suspected of promoting colorectal carcinogenesis when intestinal E. . Natural active have not been isolated, how they induce DNA damage in eukaryotic host cell is poorly characterized. Here, we show that strands cross-linked covalently exposed enterobacteria producing colibactins. cross-linking abrogated a clbP mutant unable deacetylate precolibactins or adding colibactin self-resistance protein ClbS, confirming involvement mature forms A similar mechanism observed cellulo where interstrand cross-links detected cultured human cells colibactin-producing bacteria. The intoxicated exhibit replication stress, activation ataxia-telangiectasia Rad3-related kinase (ATR), recruitment cross-link repair Fanconi anemia D2 (FANCD2) protein. In contrast, inhibition ATR knockdown FANCD2 reduces survival findings demonstrate critical colibactin-induced infected cells. IMPORTANCE Colorectal cancer third-most-common cause death. addition known risk such high-fat diets alcohol consumption, bacteria proposed play role colon development. using transient infections with showed directly generate Such lesions into double-strand breaks during response. cross-links, akin those induced widely used anticancer drugs, both severely mutagenic profoundly cytotoxic lesions. This finding direct induction bacterium should facilitate delineating engineering new agents.

Language: Английский

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Exploiting DNA Replication Stress for Cancer Treatment

Cancer Research, Journal Year: 2019, Volume and Issue: 79(8), P. 1730 - 1739

Published: April 9, 2019

Complete and accurate DNA replication is fundamental to cellular proliferation genome stability. Obstacles that delay, prevent, or terminate cause the phenomena termed stress. Cancer cells exhibit chronic stress due loss of proteins protect repair stressed forks continuous proliferative signaling, providing an exploitable therapeutic vulnerability in tumors. Here, we outline current pending approaches leveraging tumor-specific as a target, addition challenges associated with such therapies. We discuss how modulates cell-intrinsic innate immune response highlight integration immunotherapies. Together, exploiting for cancer treatment seems be promising strategy it provides selective means eliminating tumors, advances our knowledge lessons learned from therapies use, are moving toward honing potential targeting clinic.

Language: Английский

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The Plant DNA Damage Response: Signaling Pathways Leading to Growth Inhibition and Putative Role in Response to Stress Conditions

Frontiers in Plant Science, Journal Year: 2019, Volume and Issue: 10

Published: May 17, 2019

Maintenance of genome integrity is a key issue for all living organisms. Cells are constantly exposed to DNA damage due replication or transcription, cellular metabolic activities leading the production Reactive Oxygen Species (ROS) even exposure damaging agents such as UV light. However, genomes remain extremely stable, thanks permanent repair lesions. One mechanism contributing stability Damage Response (DDR) that activates pathways, and in case proliferating cells, stops cell division until complete. The signalling mechanisms DDR quite well conserved between organisms including plants where they have been investigated into detail over past 20 years. In this review we summarize acquired knowledge recent advances regarding control cycle progression. Studying plant particularly interesting because their mode development lifestyle. Indeed, develop largely post-embryonically, form new organs through activity meristems which cells retain ability proliferate. addition, sessile permanently adverse conditions could potentially induce types meristems. second part discuss findings connecting responses biotic abiotic stresses.

Language: Английский

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Targeting replication stress in cancer therapy

Nature Reviews Drug Discovery, Journal Year: 2022, Volume and Issue: 22(1), P. 38 - 58

Published: Oct. 6, 2022

Language: Английский

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FANCM limits ALT activity by restricting telomeric replication stress induced by deregulated BLM and R-loops

Nature Communications, Journal Year: 2019, Volume and Issue: 10(1)

Published: May 28, 2019

Abstract Telomerase negative immortal cancer cells elongate telomeres through the Alternative Lengthening of Telomeres (ALT) pathway. While sustained telomeric replicative stress is required to maintain ALT, it might also lead cell death when excessive. Here, we show that ATPase/translocase activity FANCM keeps in check specifically ALT cells. When depleted cells, become dysfunctional, and stop proliferating die. depletion increases ALT-associated marks de novo synthesis DNA. Depletion BLM helicase reduces replication proliferation defects induced by inactivation. Finally, unwinds R-loops vitro suppresses their accumulation Overexpression RNaseH1 completely abolishes remaining codepleted for BLM. Thus, allows controlled limiting toxicity uncontrolled R-loops.

Language: Английский

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Chemotherapy Induces Senescence-Like Resilient Cells Capable of Initiating AML Recurrence

Cancer Discovery, Journal Year: 2021, Volume and Issue: 11(6), P. 1542 - 1561

Published: Jan. 26, 2021

Patients with acute myeloid leukemia (AML) frequently relapse after chemotherapy, yet the mechanism by which AML reemerges is not fully understood. Herein, we show that primary cells enter a senescence-like phenotype following chemotherapy in vitro and vivo. This accompanied induction of senescence/inflammatory embryonic diapause transcriptional programs, downregulation MYC stem cell genes. Single-cell RNA sequencing suggested depletion vivo, enrichment for subpopulations distinct cells. senescence effect was transient conferred superior colony-forming engraftment potential. Entry into this dependent on ATR, persistence severely impaired ATR inhibitors. Altogether, propose facilitated resilience occurs regardless their status. Upon recovery, these post-senescence give rise to relapsed AMLs increased SIGNIFICANCE: Despite entering complete remission many patients AML. Thus, there an urgent need understand development targeted treatments improve outcome. Here, identified through can survive repopulate leukemia.This article highlighted In Issue feature, p. 1307.

Language: Английский

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