Eukaryotic error-prone DNA polymerases: The presumed roles in replication, repair, and mutagenesis

Vm, Krutiakov

doi:10.1134/s0026893306010018

Cited by 18 publications

(12 citation statements)

References 66 publications

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“…Note that ε is generally considered small, 74 although recent experimental evidence regarding error-prone DNA polymerases suggests that cancer cells may have increased mutation rates as a result of the overexpression of such polymerases. 75-77 For example, in Krutyakov, 75 mutation rates as a result of such polymerases are characterized by probabilities as high as 7.5 × 10 −1 per base substitution, and it is known that many point mutations in cancer arise from these DNA polymerases. 77 For this work, we adopt the notion that random point mutations that lead to drug resistance are rare, and that drug-induced resistance occurs on much quicker time scales 41 ; therefore, we will assume that α > ε with u = O (1) in our analysis of Equations 1 and 2.…”

Section: Methodsmentioning

confidence: 99%

Mathematical Approach to Differentiate Spontaneous and Induced Evolution to Drug Resistance During Cancer Treatment

Greene

Gevertz

Sontag

2019

JCO Clinical Cancer Informatics

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PurposeDrug resistance is a major impediment to the success of cancer treatment. Resistance is typically thought to arise from random genetic mutations, after which mutated cells expand via Darwinian selection. However, recent experimental evidence suggests that progression to drug resistance need not occur randomly, but instead may be induced by the treatment itself via either genetic changes or epigenetic alterations. This relatively novel notion of resistance complicates the already challenging task of designing effective treatment protocols.Materials and MethodsTo better understand resistance, we have developed a mathematical modeling framework that incorporates both spontaneous and drug-induced resistance.ResultsOur model demonstrates that the ability of a drug to induce resistance can result in qualitatively different responses to the same drug dose and delivery schedule. We have also proven that the induction parameter in our model is theoretically identifiable and propose an in vitro protocol that could be used to determine a treatment’s propensity to induce resistance.

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Section: Methodsmentioning

confidence: 99%

Mathematical Approach to Differentiate Spontaneous and Induced Evolution to Drug Resistance During Cancer Treatment

Greene

Gevertz

Sontag

2019

JCO Clinical Cancer Informatics

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“…Note however that recent experimental evidence into error prone DNA polymerases suggests that cancer cells may have increased mutation rates due to the over-expression of such polymerases [41,54,42]. For example, in [41], mutation rates due to such polymerases are characterized by probabilities as high as 7.5 × 10 −1 per base substitution, and it is known that many point mutations in cancer arise from these DNA polymerases [42]. This is indeed an interesting phenomenon which could be studied using our model, but for this work we adopt the classical notion that random point mutations leading to drug resistance are rare.…”

Section: General Modelmentioning

confidence: 99%

“…As compartment R g represents drug-resistant cells arising via spontaneous genetic mutations, the transition rate 1 S is independent of treatment, where 1 is generally considered small [50]. Note however that recent experimental evidence into error prone DNA polymerases suggests that cancer cells may have increased mutation rates due to the over-expression of such polymerases [41,54,42]. For example, in [41], mutation rates due to such polymerases are characterized by probabilities as high as 7.5 × 10 −1 per base substitution, and it is known that many point mutations in cancer arise from these DNA polymerases [42].…”

Section: General Modelmentioning

confidence: 99%

A mathematical approach to differentiate spontaneous and induced evolution to drug resistance during cancer treatment

Greene

Gevertz

Sontag

2017

Preprint

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Resistance to chemotherapy is a major impediment to the successful treatment of cancer. Classically, resistance has been thought to arise primarily through random genetic mutations, after which mutated cells expand via Darwinian selection. However, recent experimental evidence suggests that the progression to drug resistance need not occur randomly, but instead may be induced by the therapeutic agent itself. This process of resistance induction can be a result of genetic changes, or can occur through epigenetic alterations that cause otherwise drug-sensitive cancer cells to undergo phenotype switching. This relatively novel notion of resistance further complicates the already challenging task of designing treatment protocols that minimize the risk of developing drug resistance. In an effort to better understand resistance to treatment, we have developed a mathematical modeling framework that incorporates both random and drug-induced resistance. Our model demonstrates that the ability (or lack thereof) of a drug to induce resistance can result in qualitatively different responses to the same drug dose and delivery schedule. The importance of induced resistance in treatment response led us to ask if, in our model, one can determine the resistance induction rate of a drug for a given treatment protocol. Not only could we prove that the induction parameter in our model is theoretically identifiable, we have also proposed a possible in vitro protocol which could potentially be used to determine a treatment's propensity to induce resistance. (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/235150 doi: bioRxiv preprint first posted online Dec. 15, 2017; Tumor resistance to chemotherapy and targeted drugs is a major cause of treatment failure. Both molecular and microenvironmental factors have been implicated in the development of drug resistance [34]. As an example of molecular resistance, the upregulation of drug efflux transporters can prevent sufficiently high intracellular drug accumulation, limiting treatment efficacy [31]. Other molecular causes of drug resistance include modification of drug targets, enhanced DNA damage repair mechanisms, dysregulation of apoptotic pathways, and the presence of cancer stem cells [31,17,34,78,81]. The irregular tumor vasculature which results in inconsistent drug distribution and hypoxia is an example of a microenvironmental factor that impacts drug resistance [76]. Other characteristics of the tumor microenvironment that influence drug resistance include regions of acidity, immune cell infiltration and activation, and the tumor stroma [27,76,56,15,34,55].Research continues to shed light on the multitude of factors that contribute to cancer drug resistance. Mathematical modeling studies in particular have been used to explore both broad and detailed aspects of cancer drug resistance, as reviewed in [43,7,25]. The fundamental ques...

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“…7 Mutations occur during error-prone and SOS synthesis. [8][9][10][11] They cause targeted base substitution mutations 12,13 targeted insertions targeted deletions, targeted complex mutations and targeted delayed mutations. [14][15][16][17][18][19] Only 5-12 % of cis-syn cyclobutane pyrimidine dimers result in mutations.…”

mentioning

confidence: 99%

“…20 Mutations occur opposite the cyclobutane pyrimidine dimers is termed targeted mutations. [8][9][10][11]20,21 Mutations are formed in the vicinity of the damage are termed untargeted mutations. 22 Long-wave ultraviolet UVA light can cause delayed mutations.…”

mentioning

confidence: 99%

Paradigm change in mutagenesis: polymerase tautomeric models for targeted, delayed and untargeted ultraviolet mutagenesis during error plication of double stranded DNA, containing cis-syn cyclobutane thymine dimers or thymine in rare tautomeric forms

Grebneva¹

2019

IJMBOA

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Eukaryotic error-prone DNA polymerases: The presumed roles in replication, repair, and mutagenesis

Cited by 18 publications

References 66 publications

Mathematical Approach to Differentiate Spontaneous and Induced Evolution to Drug Resistance During Cancer Treatment

Mathematical Approach to Differentiate Spontaneous and Induced Evolution to Drug Resistance During Cancer Treatment

A mathematical approach to differentiate spontaneous and induced evolution to drug resistance during cancer treatment

Paradigm change in mutagenesis: polymerase tautomeric models for targeted, delayed and untargeted ultraviolet mutagenesis during error plication of double stranded DNA, containing cis-syn cyclobutane thymine dimers or thymine in rare tautomeric forms

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