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Mechanisms of Global and Region-Specific Control of Mutagenesis

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Genetics, Evolution and Radiation

Abstract

The rate of mutations in each site of a eukaryotic genome depends on a plethora of factors: nucleotides pools, asymmetry and timing of replication , types of DNA damage and parameters of its repair , translesion DNA synthesis and structure of chromatin. Studies of mutation mechanisms, traditionally performed with model systems, are currently boosted by revolutionary analysis of mutation landscapes of cancer genomes. Etiology of familial and sporadic cancers is connected to mutations in DNA polymerase and mismatch repair genes that unevenly lower the accuracy of replication in different chromosomal regions. Transient appearance of single-stranded DNA makes some genomic sites vulnerable to spontaneous or enzymatic deamination by AID/APOBECs that lead to clustered mutations called kataegis. Of special significance is an impact of cell ploidy on mutagenesis outcomes. Haploid cells with the highest levels of mutagenesis die due to lethal mutations. Descendants of hypermutable cells in diploids, where lethal recessive mutations load is tolerated, could be recovered and analyzed, permitting a glimpse into hitherto hidden mechanisms of mutagenesis.

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Acknowledgments

We are thankful Dr. V.L. Korogodina and Dr. S.G. Inge-Vechtomov for the invitation to present the lecture that was a starting point of work on the current review at the IV International meeting dedicated to the 115th anniversary of the birth of N.W.Timofeeff-Ressovsky and his international scientific school in Saint-Petersburg. We are grateful to Dr. Erik Johansson and Dr. Peter Burgers for sharing preparations of yeast DNA pols. The work was supported by UNMC Eppley Institute Pilot grant in 2014–2015, grant RFBR # 15-04-08625 and Research Grant of SPbU #1.38.426.2015

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Authors and Affiliations

  1. Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, USA

    Youri I. Pavlov, Artem G. Lada, Corinn Grabow & Elena I. Stepchenkova

  2. Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, USA

    Youri I. Pavlov

  3. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, USA

    Youri I. Pavlov

  4. Department of Microbiology and Molecular Genetics, University of California, Davis, USA

    Artem G. Lada

  5. Human Genetics Laboratory, Munroe-Meyer Institute for Genetics and Rehabilitation, UNMC, Omaha, USA

    Corinn Grabow

  6. Saint Petersburg Branch of Vavilov Institute of General Genetics, St Petersburg University, St Petersburg, Russia

    Elena I. Stepchenkova

  7. Department of Genetics, St Petersburg University, St Petersburg, Russia

    Elena I. Stepchenkova

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  1. Youri I. Pavlov
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  2. Artem G. Lada
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  3. Corinn Grabow
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  4. Elena I. Stepchenkova
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Corresponding author

Correspondence to Youri I. Pavlov .

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Editors and Affiliations

  1. Joint Institute for Nuclear Research, Dubna, Moscow Region, Russia

    Victoria L. Korogodina

  2. Department of Medical Physics and Applied Radiation Sciences, McMaster University, Hamilton, Ontario, Canada

    Carmel E Mothersill

  3. Genetics and Biotechnology, St. Petersburg State University, St. Petersburg, Russia

    Sergey G. Inge-Vechtomov

  4. Department of Medical Physics and Applied Radiation Sciences, McMaster University, Hamilton, Ontario, Canada

    Colin B. Seymour

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Pavlov, Y.I., Lada, A.G., Grabow, C., Stepchenkova, E.I. (2016). Mechanisms of Global and Region-Specific Control of Mutagenesis. In: Korogodina, V., Mothersill, C., Inge-Vechtomov, S., Seymour, C. (eds) Genetics, Evolution and Radiation. Springer, Cham. https://doi.org/10.1007/978-3-319-48838-7_6

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