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The fission yeast FHIT homolog affects checkpoint control of proliferation and is regulated by mitochondrial electron transport.

Authors
  • Sjölander, Johanna J1
  • Sunnerhagen, Per1
  • 1 Department of Chemistry and Molecular Biology, Lundberg Laboratory, University of Gothenburg, P.O. Box 462, Göteborg, SE-405 30, Sweden. , (Sweden)
Type
Published Article
Journal
Cell Biology International
Publisher
Wiley (John Wiley & Sons)
Publication Date
Sep 20, 2019
Identifiers
DOI: 10.1002/cbin.11241
PMID: 31538680
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Genetic analysis has strongly implicated human FHIT (Fragile Histidine Triad) as a tumor suppressor gene, being mutated in a large proportion of early-stage cancers. The functions of the FHIT protein have, however, remained elusive. Here, we investigated aph1+ , the fission yeast homolog of FHIT, for functions related to checkpoint control and oxidative metabolism. In sublethal concentrations of DNA damaging agents, aph1Δ mutants grew with a substantially shorter lag phase. In aph1Δ mutants carrying a hypomorphic allele of cds1 (the fission yeast homolog of Chk2), in addition, increased chromosome fragmentation and missegregation were found. We also found that under hypoxia or impaired electron transport function, the Aph1 protein level was strongly depressed. Previously, FHIT has been linked to regulation of the human 9-1-1 checkpoint complex constituted by Hus1, Rad1, and Rad9. In Schizosaccharomyces pombe, the levels of all three 9-1-1 proteins are all downregulated by hypoxia in similarity with Aph1. Moreover, deletion of the aph1+ gene reduced the Rad1 protein level, indicating a direct relationship between these two proteins. We conclude that the fission yeast FHIT homolog has a role in modulating DNA damage checkpoint function, possibly through an effect on the 9-1-1 complex, and that this effect may be critical under conditions of limiting oxidative metabolism and reoxygenation. © 2019 The Authors. Cell Biology International published by John Wiley & Sons Ltd on behalf of International Federation of Cell Biology.

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