The PTEN phosphatase functions cooperatively with the Fanconi anemia proteins in DNA crosslink repair

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Vuono, EA; Mukherjee, A; Vierra, DA; Adroved, MM; Hodson, C; Deans, AJ; Howlett, NGDate
2016-11-07Source Title
Scientific ReportsPublisher
NATURE PUBLISHING GROUPUniversity of Melbourne Author/s
Deans, AndrewAffiliation
Medicine and RadiologyMetadata
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Vuono, E. A., Mukherjee, A., Vierra, D. A., Adroved, M. M., Hodson, C., Deans, A. J. & Howlett, N. G. (2016). The PTEN phosphatase functions cooperatively with the Fanconi anemia proteins in DNA crosslink repair. SCIENTIFIC REPORTS, 6 (1), https://doi.org/10.1038/srep36439.Access Status
Open AccessAbstract
Fanconi anemia (FA) is a genetic disease characterized by bone marrow failure and increased cancer risk. The FA proteins function primarily in DNA interstrand crosslink (ICL) repair. Here, we have examined the role of the PTEN phosphatase in this process. We have established that PTEN-deficient cells, like FA cells, exhibit increased cytotoxicity, chromosome structural aberrations, and error-prone mutagenic DNA repair following exposure to ICL-inducing agents. The increased ICL sensitivity of PTEN-deficient cells is caused, in part, by elevated PLK1 kinase-mediated phosphorylation of FANCM, constitutive FANCM polyubiquitination and degradation, and the consequent inefficient assembly of the FA core complex, FANCD2, and FANCI into DNA repair foci. We also establish that PTEN function in ICL repair is dependent on its protein phosphatase activity and ability to be SUMOylated, yet is independent of its lipid phosphatase activity. Finally, via epistasis analysis, we demonstrate that PTEN and FANCD2 function cooperatively in ICL repair.
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