Inhibition of mutagenic translesion synthesis: A possible strategy for improving chemotherapy?

Yamanaka, Kinrin; Chatterjee, Nimrat; Hemann, Michael T.; Walker, Graham C.

doi:10.1371/journal.pgen.1006842

Cited by 78 publications

(94 citation statements)

References 116 publications

(53 reference statements)

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“…These results suggest that targeting Pol h and ATR in combination may be a viable, new treatment strategy for patients with cancer. Indeed, TLS polymerases such as Pol h are emerging as key enzymes mediating tumor cell responses to chemotherapy (45). Recently, the Rev3 subunit of Pol z was identified as a synthetic lethal partner with combined ATR inhibition and cisplatin treatment (46).…”

Section: Discussionmentioning

confidence: 99%

DNA Polymerase Eta Prevents Tumor Cell-Cycle Arrest and Cell Death during Recovery from Replication Stress

et al. 2018

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Neoplastic transformation and genome instability are enhanced by replication stress, conditions that slow or stall DNA replication forks. Consequently, cancer cells require multiple enzymes and checkpoint signaling pathways to mitigate replication stress for their viability and proliferation. Targeting proteins that enhance cancer cell survival during replication stress is a recent approach in clinical strategies, especially when targets produce synthetic lethality. DNA polymerase eta (Pol h) has many key functions in genome stability, particularly for translesion synthesis. Here we demonstrate that endogenous Pol h displays significant protein induction and forms intense foci throughout the nucleus in response to replication stress induced by drugs that do not directly form DNA adducts. During replication stress, Pol h-deficient cells displayed hyperactivation of the ATR replication checkpoint and arrested late in the cell cycle. During recovery from replication stress, Pol h-deficient cells continue to display aberrant phenotypes, including delayed cell-cycle progression, apoptosis, and cell survival. Depletion or inhibition of ATR was synthetically lethal with Pol h deficiency, particularly when tumor cells were treated with replication stress-inducing drugs. Together our data expand knowledge of the cellular environments that increase endogenous Pol h expression beyond DNA damaging agents and demonstrate that Pol h regulation is central to the replication stress response. Because Pol h is aberrantly expressed in several tumor types, our results are critical for developing more effective chemotherapy approaches and identify coinhibition of Pol h and ATR as a potential therapeutic strategy.Significance: This study demonstrates that replication stress upregulates Pol h (POLH) in tumor cells and reveals a role for Pol h in tumor cell recovery following replication stress. Cancer Res; 78(23); 6549-60. Ó2018 AACR.

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Section: Discussionmentioning

confidence: 99%

DNA Polymerase Eta Prevents Tumor Cell-Cycle Arrest and Cell Death during Recovery from Replication Stress

et al. 2018

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“…[1][2][3] While this mechanism is responsible for rescuing cells during activer eplication, it does so at the expense of an increased mutationr ate in the surviving cells. [3,6,7] In the context of cancert reatment, TLS promotes tumor cell survival in the presence of first-line genotoxic chemotherapies, which can ultimately lead to acquired resistance to the first-line therapy. [3,6,7] In the context of cancert reatment, TLS promotes tumor cell survival in the presence of first-line genotoxic chemotherapies, which can ultimately lead to acquired resistance to the first-line therapy.…”

Section: Introductionmentioning

confidence: 99%

“…[3,6,7] In the context of cancert reatment, TLS promotes tumor cell survival in the presence of first-line genotoxic chemotherapies, which can ultimately lead to acquired resistance to the first-line therapy. [3,6,7] Proper TLS function requires the concertede fforto fm ultiple DNA polymerases in complex with the DNA clamp PCNA to controlas eries of switching eventst hat ensure this mechanism is only recruited to rescue replication stalled at DNA lesions. [3,6,7] Proper TLS function requires the concertede fforto fm ultiple DNA polymerases in complex with the DNA clamp PCNA to controlas eries of switching eventst hat ensure this mechanism is only recruited to rescue replication stalled at DNA lesions.…”

Section: Introductionmentioning

confidence: 99%

“…[4,5] The role of TLS in promoting cell survival has resultedi ni ts emergencea s ap otential target for the development of an ew class of anticancer agents. [3,6,7] In the context of cancert reatment, TLS promotes tumor cell survival in the presence of first-line genotoxic chemotherapies, which can ultimately lead to acquired resistance to the first-line therapy. [4,5] Disruption of TLS can sensitize cancers to genotoxic agents and decrease mutagenesisi n tumors,s uggesting that combination therapy with aT LS inhibitor could enhancet he efficacy of first-line agents and prevent chemoresistance.…”

Section: Introductionmentioning

confidence: 99%

“…[4,5] Disruption of TLS can sensitize cancers to genotoxic agents and decrease mutagenesisi n tumors,s uggesting that combination therapy with aT LS inhibitor could enhancet he efficacy of first-line agents and prevent chemoresistance. [3,6,7] Proper TLS function requires the concertede fforto fm ultiple DNA polymerases in complex with the DNA clamp PCNA to controlas eries of switching eventst hat ensure this mechanism is only recruited to rescue replication stalled at DNA lesions. [1,2,8,9] Severalo ft hese switching events are mediated by protein-protein interactions (PPIs) between the C-terminal domain of the Y-familyp olymerase Rev1 (Rev1-CT) and the Rev1 interacting regions (RIR) from the Y-familyp olymerases polh,p olk,p oli,a nd polz.…”

Section: Introductionmentioning

confidence: 99%

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Virtual Pharmacophore Screening Identifies Small‐Molecule Inhibitors of the Rev1‐CT/RIR Protein–Protein Interaction

et al. 2019

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Translesion synthesis (TLS) has emerged as a mechanism through which several forms of cancer develop acquired resistance to first‐line genotoxic chemotherapies by allowing replication to continue in the presence of damaged DNA. Small molecules that inhibit TLS hold promise as a novel class of anticancer agents that can serve to enhance the efficacy of these front‐line therapies. We previously used a structure‐based rational design approach to identify the phenazopyridine scaffold as an inhibitor of TLS that functions by disrupting the protein–protein interaction (PPI) between the C‐terminal domain of the TLS DNA polymerase Rev1 (Rev1‐CT) and the Rev1 interacting regions (RIR) of other TLS DNA polymerases. To continue the identification of small molecules that disrupt the Rev1‐CT/RIR PPI, we generated a pharmacophore model based on the phenazopyridine scaffold and used it in a structure‐based virtual screen. In vitro analysis of promising hits identified several new chemotypes with the ability to disrupt this key TLS PPI. In addition, several of these compounds were found to enhance the efficacy of cisplatin in cultured cells, highlighting their anti‐TLS potential.

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Structure‐Based Drug Design of Phenazopyridine Derivatives as Inhibitors of Rev1 Interactions in Translesion Synthesis

et al. 2021

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Rev1 is a protein scaffold of the translesion synthesis (TLS) pathway, which employs low‐fidelity DNA polymerases for replication of damaged DNA. The TLS pathway helps cancers tolerate DNA damage induced by genotoxic chemotherapy, and increases mutagenesis in tumors, thus accelerating the onset of chemoresistance. TLS inhibitors have emerged as potential adjuvant drugs to enhance the efficacy of first‐line chemotherapy, with the majority of reported inhibitors targeting protein‐protein interactions (PPIs) of the Rev1 C‐terminal domain (Rev1‐CT). We previously identified phenazopyridine (PAP) as a scaffold to disrupt Rev1‐CT PPIs with Rev1‐interacting regions (RIRs) of TLS polymerases. To explore the structure‐activity relationships for this scaffold, we developed a protocol for co‐crystallization of compounds that target the RIR binding site on Rev1‐CT with a triple Rev1‐CT/Rev7R124A/Rev3‐RBM1 complex, and solved an X‐ray crystal structure of Rev1‐CT bound to the most potent PAP analogue. The structure revealed an unexpected binding pose of the compound and informed changes to the scaffold to improve its affinity for Rev1‐CT. We synthesized eight additional PAP derivatives, with modifications to the scaffold driven by the structure, and evaluated their binding to Rev1‐CT by microscale thermophoresis (MST). Several second‐generation PAP derivatives showed an affinity for Rev1‐CT that was improved by over an order of magnitude, thereby validating the structure‐based assumptions that went into the compound design.

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Inhibition of mutagenic translesion synthesis: A possible strategy for improving chemotherapy?

Cited by 78 publications

References 116 publications

DNA Polymerase Eta Prevents Tumor Cell-Cycle Arrest and Cell Death during Recovery from Replication Stress

DNA Polymerase Eta Prevents Tumor Cell-Cycle Arrest and Cell Death during Recovery from Replication Stress

Virtual Pharmacophore Screening Identifies Small‐Molecule Inhibitors of the Rev1‐CT/RIR Protein–Protein Interaction

Structure‐Based Drug Design of Phenazopyridine Derivatives as Inhibitors of Rev1 Interactions in Translesion Synthesis

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