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Error-prone DNA polymerase and oxidative stress increase the incidences of A to G mutations in tumors.

ABSTRACT: Mutational processes for A?G mutations in tumors are not well understood. To uncover the mutational mechanisms, we analyzed molecular profiles of more than 9,000 tumor samples from The Cancer Genome Atlas (TCGA). The present study found that error-prone DNA polymerases were involved in stomach tumors with high fraction of A?G mutations. High levels of apoptosis in kidney cancers and high levels of energy metabolism in thyroid cancers increased A?G mutation rate, which was associated with high oxidative stress. We also found that the frequencies of RAS gene mutations were increased in thyroid cancers with high level of energy metabolism because of high-frequency A?G mutations.

SUBMITTER: Lin J

PROVIDER: S-EPMC5542174 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Error-prone DNA polymerase and oxidative stress increase the incidences of A to G mutations in tumors.

Lin Jiannan J Shi Tieliu T

Oncotarget 20170701 28

Mutational processes for A→G mutations in tumors are not well understood. To uncover the mutational mechanisms, we analyzed molecular profiles of more than 9,000 tumor samples from The Cancer Genome Atlas (TCGA). The present study found that error-prone DNA polymerases were involved in stomach tumors with high fraction of A→G mutations. High levels of apoptosis in kidney cancers and high levels of energy metabolism in thyroid cancers increased A→G mutation rate, which was associated with high ox ...[more]

PMID: 28582771

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Project description:UnlabelledEscherichia coli's DNA polymerase IV (Pol IV/DinB), a member of the Y family of error-prone polymerases, is induced during the SOS response to DNA damage and is responsible for translesion bypass and adaptive (stress-induced) mutation. In this study, the localization of Pol IV after DNA damage was followed using fluorescent fusions. After exposure of E. coli to DNA-damaging agents, fluorescently tagged Pol IV localized to the nucleoid as foci. Stepwise photobleaching indicated ∼60% of the foci consisted of three Pol IV molecules, while ∼40% consisted of six Pol IV molecules. Fluorescently tagged Rep, a replication accessory DNA helicase, was recruited to the Pol IV foci after DNA damage, suggesting that the in vitro interaction between Rep and Pol IV reported previously also occurs in vivo. Fluorescently tagged RecA also formed foci after DNA damage, and Pol IV localized to them. To investigate if Pol IV localizes to double-strand breaks (DSBs), an I-SceI endonuclease-mediated DSB was introduced close to a fluorescently labeled LacO array on the chromosome. After DSB induction, Pol IV localized to the DSB site in ∼70% of SOS-induced cells. RecA also formed foci at the DSB sites, and Pol IV localized to the RecA foci. These results suggest that Pol IV interacts with RecA in vivo and is recruited to sites of DSBs to aid in the restoration of DNA replication.ImportanceDNA polymerase IV (Pol IV/DinB) is an error-prone DNA polymerase capable of bypassing DNA lesions and aiding in the restart of stalled replication forks. In this work, we demonstrate in vivo localization of fluorescently tagged Pol IV to the nucleoid after DNA damage and to DNA double-strand breaks. We show colocalization of Pol IV with two proteins: Rep DNA helicase, which participates in replication, and RecA, which catalyzes recombinational repair of stalled replication forks. Time course experiments suggest that Pol IV recruits Rep and that RecA recruits Pol IV. These findings provide in vivo evidence that Pol IV aids in maintaining genomic stability not only by bypassing DNA lesions but also by participating in the restoration of stalled replication forks.

Dataset Information

Error-prone DNA polymerase and oxidative stress increase the incidences of A to G mutations in tumors.

Publications

Error-prone DNA polymerase and oxidative stress increase the incidences of A to G mutations in tumors.

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