Genetic variants and mutations of PPM1D control the response to DNA damage

Crissy Dudgeon, Sathyavageeswaran Shreeram, Kan Tanoue, Sharlyn J. Mazur, Ahmed Sayadi, Robert C. Robinson, Ettore Appella, Dmitry V. Bulavin

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

The Wip1 phosphatase is an oncogene that is overexpressed in a variety of primary human cancers. We were interested in identifying genetic variants that could change Wip1 activity. We identified 3 missense SNPs of the human Wip1 phosphatase, L120F, P322Q, and I496V confer a dominant-negative phenotype. On the other hand, in primary human cancers, PPM1D mutations commonly result in a gain-of-function phenotype, leading us to identify a hot-spot truncating mutation at position 525. Surprisingly, we also found a significant number of loss-of-function mutations of PPM1D in primary human cancers, both in the phosphatase domain and in the C terminus. Thus, PPM1D has evolved to generate genetic variants with lower activity, potentially providing a better fitness for the organism through suppression of multiple diseases. In cancer, however, the situation is more complex, and the presence of both activating and inhibiting mutations requires further investigation to understand their contribution to tumorigenesis.

Original languageEnglish
Pages (from-to)2656-2664
Number of pages9
JournalCell Cycle
Volume12
Issue number16
DOIs
Publication statusPublished - Aug 15 2013
Externally publishedYes

Keywords

  • ATM
  • Chk2
  • Genetic variants
  • Human cancer
  • Mutations
  • PPM1D
  • Wip1

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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  • Cite this

    Dudgeon, C., Shreeram, S., Tanoue, K., Mazur, S. J., Sayadi, A., Robinson, R. C., Appella, E., & Bulavin, D. V. (2013). Genetic variants and mutations of PPM1D control the response to DNA damage. Cell Cycle, 12(16), 2656-2664. https://doi.org/10.4161/cc.25694