REV1-Polζ maintains the viability of homologous recombination-deficient cancer cells through mutagenic repair of PRIMPOL-dependent ssDNA gaps

Taglialatela, Angelo; Leuzzi, Giuseppe; Sannino, Vincenzo; Cuella-Martin, Raquel; Huang, Jingshu; Wu-Baer, Foon; Baer, Richard; Costanzo, Vincenzo; Ciccia, Alberto

doi:10.1016/j.molcel.2021.08.016

Cited by 91 publications

(109 citation statements)

References 107 publications

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“…Single-stranded DSGs within DNA fibers are sensitive to S1-nuclease activity and can thus be indirectly measured by the extent of DNA fragmentation [ 92 ]. The high frequency of DSGs detected in cells depleted for BRCA2 or other RAD51 mediator proteins (RAD51 paralogs) reinforced earlier observations that DSGs are repaired by HR in a RAD51-dependent manner [ 69 , 81 , 93 ]. DSG formation is induced by common DNA lesions, causing discontinuous DNA replication (e.g., unrepaired base damage caused by oxidative stress, UV-induced pyrimidine dimers, bulky DNA adducts induced by carcinogens, such as benzo-[a]-pyrene metabolites and other forms of DNA base damage) as well as DNA repair processes behind the fork (e.g., nicking of the sugar-phosphate backbone during base excision repair, nucleotide excision repair, and mismatch repair) [ 83 ].…”

Section: Hr As An Intrinsic Safeguard Of Dna Replication In Mammalian Somatic Cellssupporting

confidence: 68%

Homologous Recombination as a Fundamental Genome Surveillance Mechanism during DNA Replication

Spies

Polasek-Sedlackova

Lukáš

et al. 2021

Genes

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Accurate and complete genome replication is a fundamental cellular process for the proper transfer of genetic material to cell progenies, normal cell growth, and genome stability. However, a plethora of extrinsic and intrinsic factors challenge individual DNA replication forks and cause replication stress (RS), a hallmark of cancer. When challenged by RS, cells deploy an extensive range of mechanisms to safeguard replicating genomes and limit the burden of DNA damage. Prominent among those is homologous recombination (HR). Although fundamental to cell division, evidence suggests that cancer cells exploit and manipulate these RS responses to fuel their evolution and gain resistance to therapeutic interventions. In this review, we focused on recent insights into HR-mediated protection of stress-induced DNA replication intermediates, particularly the repair and protection of daughter strand gaps (DSGs) that arise from discontinuous replication across a damaged DNA template. Besides mechanistic underpinnings of this process, which markedly differ depending on the extent and duration of RS, we highlight the pathophysiological scenarios where DSG repair is naturally silenced. Finally, we discuss how such pathophysiological events fuel rampant mutagenesis, promoting cancer evolution, but also manifest in adaptative responses that can be targeted for cancer therapy.

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Section: Hr As An Intrinsic Safeguard Of Dna Replication In Mammalian Somatic Cellssupporting

confidence: 68%

Homologous Recombination as a Fundamental Genome Surveillance Mechanism during DNA Replication

Spies

Polasek-Sedlackova

Lukáš

et al. 2021

Genes

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“…Recent findings identified a novel role of the BRCA pathway in suppressing accumulation of ssDNA gaps upon replication stress, ( 34 , 48–53 ). Using a previously-described assay for measuring ssDNA gap accumulation in newly-replicated DNA, namely the BrdU alkaline comet assay ( 34 , 54 ), we found that, indeed, low-dose HU treatment increased ssDNA accumulation in HeLa-BRCA2 KO cells compared to wildtype cells (Figure 5D ).…”

Section: Resultsmentioning

confidence: 99%

“…Mechanistically, chemoresistance in BRCA-deficient cells has been associated with restoration of DSB repair, with protection against nucleolytic degradation of stalled replication forks, and more recently with suppression of ssDNA gap formation ( 16–18 , 22–30 , 34 , 48–53 ). We found that loss of MED12 in BRCA-deficient cells increases HR-mediated DSB repair, suppresses nascent strand degradation upon fork stalling, and reduces the accumulation of ssDNA gaps.…”

Section: Discussionmentioning

confidence: 99%

Loss of MED12 activates the TGFβ pathway to promote chemoresistance and replication fork stability in BRCA-deficient cells

Jackson

Dhoonmoon

Hale

et al. 2021

Nucleic Acids Research

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Understanding chemoresistance mechanisms in BRCA-deficient cells will allow for identification of biomarkers for predicting tumor response to therapy, as well as the design of novel therapeutic approaches targeting this chemoresistance. Here, we show that the protein MED12, a component of the Mediator transcription regulation complex, plays an unexpected role in regulating chemosensitivity in BRCA-deficient cells. We found that loss of MED12 confers resistance to cisplatin and PARP inhibitors in both BRCA1- and BRCA2-deficient cells, which is associated with restoration of both homologous recombination and replication fork stability. Surprisingly, MED12-controlled chemosensitivity does not involve a function of the Mediator complex, but instead reflects a distinct role of MED12 in suppression of the TGFβ pathway. Importantly, we show that ectopic activation of the TGFβ pathway is enough to overcome the fork protection and DNA repair defects of BRCA-mutant cells, resulting in chemoresistance. Our work identifies the MED12-TGFβ module as an important regulator of genomic stability and chemosensitivity in BRCA-deficient cells.

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“…However, the lagging-strand is synthes which are initiated by the primosome (Figure 1E) an polymerase Pol δ (Figure 1F). Therefore, the prima carries out this task in BRCA1/2 deficient cells, a scenario involving the accumulation of DNA gaps due to PrimPol-mediated repriming (Figure 9 top right panel) [132]. This mechanism, dependent on RAD18, takes place during the G2 phase [129].…”

Section: Introduction: Primpol a New Enzyme Workingmentioning

confidence: 99%

PrimPol: A Breakthrough among DNA Replication Enzymes and a Potential New Target for Cancer Therapy

et al. 2022

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DNA replication can encounter blocking obstacles, leading to replication stress and genome instability. There are several mechanisms for evading this blockade. One mechanism consists of repriming ahead of the obstacles, creating a new starting point; in humans, PrimPol is responsible for carrying out this task. PrimPol is a primase that operates in both the nucleus and mitochondria. In contrast with convectional primases, PrimPol is a DNA primase able to initiate DNA synthesis de novo using deoxynucleotides, discriminating against ribonucleotides. In vitro, PrimPol can act as a translesion synthesis (TLS) DNA primase, elongating primers that PrimPol itself sythesizes, or as TLS DNA polymerase, elongating pre-existing primers across lesions. However, the lack of evidence for PrimPol polymerase activity in vivo suggests that PrimPol only uses its TLS abilities to facilitate priming across lesions in cells, thus acting as a TLS DNA primase. Here, we provide a comprehensive review of human PrimPol covering its biochemical properties and structure, in vivo function and regulation, and the processes that take place to fill the gap-containing lesion that PrimPol leaves behind. Finally, we explore the available data on human PrimPol expression in different tissues in physiological conditions and its role in cancer.

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REV1-Polζ maintains the viability of homologous recombination-deficient cancer cells through mutagenic repair of PRIMPOL-dependent ssDNA gaps

Cited by 91 publications

References 107 publications

Homologous Recombination as a Fundamental Genome Surveillance Mechanism during DNA Replication

Homologous Recombination as a Fundamental Genome Surveillance Mechanism during DNA Replication

Loss of MED12 activates the TGFβ pathway to promote chemoresistance and replication fork stability in BRCA-deficient cells

PrimPol: A Breakthrough among DNA Replication Enzymes and a Potential New Target for Cancer Therapy

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