Inter-genomic cross talk between mitochondria and the nucleus plays an important role in tumorigenesis.
Mitochondrial dysfunction is a hallmark of cancer cells. Consistent with this phenotype mutations in mitochondrial genome have been reported in all cancers examined to date. However, it is not clear whether mitochondrial genomic status in human cells affects nuclear genome stability and whether proteins involved in inter-genomic cross talk are involved in tumorigenesis. Using cell culture model and cybrid cell technology, we provide evidence that mitochondrial genetic status impacts nuclear genome stability in human cells. In particular our studies demonstrate 1) that depletion of mitochondrial genome (rho0) leads to chromosomal instability (CIN) reported to be present in variety of human tumors and 2) rho0 cells show transformed phenotype. Our study also demonstrates that mitochondrial genetic status plays a key role in regulation of a multifunctional protein APE1 (also known as Ref1 or HAP1) involved in transcription and DNA repair in the nucleus and the mitochondria. Interestingly we found that altered expression of APE1 in rho0 cells and tumorigenic phenotype can be reversed by exogenous transfer of wild type mitochondria in rho0 cells. Furthermore, we demonstrate that APE1 expression is altered in variety of primary tumors. Taken together, these studies suggest that inter-genomic cross talk between mitochondria and the nucleus plays an important role in tumorigenesis and that APE1 mediates this process.
Singh
Keshav K
KK
Department of Cancer Genetics, Cell and Virus Building, Room 247, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA. keshav.singh@roswellpark.org
Kulawiec
Mariola
M
Still
Ivan
I
Desouki
Mohamed M
MM
Geradts
Joseph
J
Matsui
Sei-Ichi
S
D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics*; D002869:Chromosome Aberrations; D004272:DNA, Mitochondrial / Q000235:genetics*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism; D005260:Female; D006801:Humans; D006822:Hybrid Cells; D007150:Immunohistochemistry; D008297:Male; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics*; D032681:Spectral Karyotyping; D046888:Tissue Array Analysis; D014178:Translocation, Genetic
D004272:DNA, Mitochondrial; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase