REV3L is the DNA polymerase subunit of pol 6, an enzyme involved in tolerance of genomic damage. REV3L is essential for embryonic development, for reasons that remain to be clarified. We find that Rev3L-defective mammalian cells have high rates of spontaneous chromosome instability, a feature that is also characteristic of many cancers. The PI's laboratory has developed a conditional pol zeta-null mouse, and it appears that a subset of tumors in such mice are preferentially Rev3L-null. Pol 6 may thus be an example of a specialized DNA polymerase that acts as a tumor suppressor gene. The proposed experiments will use a new combination of cellular, genetic, and mouse model approaches to test the extent to which REV3L protects cells against endogenous DNA-damaging stress and chromosomal instability, and to investigate the process of tumor development in the absence of REV3L.
The aims are (1) to test the hypothesis that REV3L enables cells to tolerate DNA damage that can disrupt chromosome integrity and interfere with cell proliferation;(2) to determine which domains of the REV3L protein are necessary for normal cell proliferation and genome stability;(3) to test whether loss of REV3L function in mice promotes tumor development.

Public Health Relevance

DNA damaging agents produce mutations that affect human health, aging, and genome instability. Our research suggests that the human DNA repair protein REV3L suppresses tumor formation by helping to prevent genome instability. Knowledge of the REV3L status of tumors could be useful in tailoring therapies, and specific interference with REV3L function could be expected to influence tumor development.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA132840-05
Application #
8403818
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Okano, Paul
Project Start
2009-01-14
Project End
2014-06-30
Budget Start
2013-01-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$291,367
Indirect Cost
$102,168
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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Schibler, Andria; Koutelou, Evangelia; Tomida, Junya et al. (2016) Histone H3K4 methylation regulates deactivation of the spindle assembly checkpoint through direct binding of Mad2. Genes Dev 30:1187-97
Lange, Sabine S; Tomida, Junya; Boulware, Karen S et al. (2016) The Polymerase Activity of Mammalian DNA Pol ζ Is Specifically Required for Cell and Embryonic Viability. PLoS Genet 12:e1005759
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Tomida, Junya; Takata, Kei-ichi; Lange, Sabine S et al. (2015) REV7 is essential for DNA damage tolerance via two REV3L binding sites in mammalian DNA polymerase ζ. Nucleic Acids Res 43:1000-11
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Lange, Sabine S; Bedford, Ella; Reh, Shelley et al. (2013) Dual role for mammalian DNA polymerase ζ in maintaining genome stability and proliferative responses. Proc Natl Acad Sci U S A 110:E687-96
Lange, Sabine S; Wittschieben, John P; Wood, Richard D (2012) DNA polymerase zeta is required for proliferation of normal mammalian cells. Nucleic Acids Res 40:4473-82

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