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Stochastic activation of a DNA damage response causes cell-to-cell mutation rate variation.

ABSTRACT: Cells rely on the precise action of proteins that detect and repair DNA damage. However, gene expression noise causes fluctuations in protein abundances that may compromise repair. For the Ada protein in Escherichia coli, which induces its own expression upon repairing DNA alkylation damage, we found that undamaged cells on average produce one Ada molecule per generation. Because production is stochastic, many cells have no Ada molecules and cannot induce the damage response until the first expression event occurs, which sometimes delays the response for generations. This creates a subpopulation of cells with increased mutation rates. Nongenetic variation in protein abundances thus leads to genetic heterogeneity in the population. Our results further suggest that cells balance reliable repair against toxic side effects of abundant DNA repair proteins.

SUBMITTER: Uphoff S

PROVIDER: S-EPMC4827329 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Stochastic activation of a DNA damage response causes cell-to-cell mutation rate variation.

Uphoff Stephan S Lord Nathan D ND Okumus Burak B Potvin-Trottier Laurent L Sherratt David J DJ Paulsson Johan J

Science (New York, N.Y.) 20160301 6277

Cells rely on the precise action of proteins that detect and repair DNA damage. However, gene expression noise causes fluctuations in protein abundances that may compromise repair. For the Ada protein in Escherichia coli, which induces its own expression upon repairing DNA alkylation damage, we found that undamaged cells on average produce one Ada molecule per generation. Because production is stochastic, many cells have no Ada molecules and cannot induce the damage response until the first expr ...[more]

PMID: 26941321

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Project description:Importance:It is necessary to understand the mechanisms of metastasis of uveal melanoma to advise patients and develop treatments for this tumor. Objective:To examine the stochastic properties of primary uveal melanoma including the mutation rate as a function of tumor size and metastatic rate relative to the type of mutation. Design, Setting, and Participants:We computed the mutation rate in different sized uveal melanomas using previously published large data sets. Tumor volume was estimated using the spherical cap method. We also calculated the metastatic rate using an updated data set of patients with uveal melanoma with known mutations in BAP1, SF3B1, and EIF1AX provided by the Rotterdam Ocular Melanoma Study Group. Data were analyzed from 2 studies, one taking place from August 25, 1970, to August 27, 2008, and the other taking place between 1993 and 2013. Data were analyzed between 2016 and 2017. Main Outcomes and Measures:Mutation rates and metastic rates. Results:Based on the 5-year metastatic rates, mutation rates ranged from 1.09 × 10-8 to 7.86 × 10-7 per cell division, using our calculation algorithm. A higher mutation rate was found for tumors with smaller thicknesses. EIF1AX mutations were not exclusive of other mutations because 2 cases with EIF1AX mutations and metastasis also had BAP1 mutations. None of the tumors with only an EIF1AX mutation metastasized. After plotting the yearly metastatic rate vs time after treatment, we observed a small peak at 1 year and a large peak at 3.5 years after treatment for BAP1 mutations, with peaks between 2 and 3 years and at 7 years for SF3B1 mutations. Conclusions and Relevance:We observed a higher mutation rate for smaller tumors, which may be explained by a greater number of cell divisions occurring during the expansion phase of smaller uveal melanomas. Regarding time to clinically detected metastases, the first 2 peaks appear to be associated with BAP1-mutated tumors and the late peak to SF3B1-mutated tumors.

Dataset Information

Stochastic activation of a DNA damage response causes cell-to-cell mutation rate variation.

Publications

Stochastic activation of a DNA damage response causes cell-to-cell mutation rate variation.

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