Defining the DNA mismatch repair-dependent apoptotic pathway in primary cells: evidence for p53-independence and involvement of centrosomal caspase 2.
Many studies have shown that DNA mismatch repair (MMR) has a role beyond that of repair in response to several types of DNA damage, including ultraviolet radiation (UV). We have demonstrated previously that the MMR-dependent component of UVB-induced apoptosis is integral to the suppression of UVB-induced tumorigenesis. Here we demonstrate that Msh6-dependent UVB-induced apoptotic pathway is both activated via the mitochondria and p53-independent. In addition, we have shown for the first time that caspase 2, an initiator caspase, localizes to the centrosomes in mitotic primary mouse embryonic fibroblasts, irrespective of MMR status and UVB treatment.
Narine
Kelly A D
KA
Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada.
Keuling
Angela M
AM
Gombos
Randi
R
Tron
Victor A
VA
Andrew
Susan E
SE
Young
Leah C
LC
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D053143:Caspase 2 / Q000378:metabolism*; D053453:Caspase 9 / Q000378:metabolism; D002457:Cell Extracts; D002478:Cells, Cultured; D018385:Centrosome / Q000201:enzymology* / Q000528:radiation effects; D045304:Cytochromes c / Q000378:metabolism; D053843:DNA Mismatch Repair / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation / Q000528:radiation effects; D053078:Membrane Potential, Mitochondrial / Q000528:radiation effects; D051379:Mice; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000201:enzymology / Q000528:radiation effects; D051718:MutS Homolog 2 Protein / Q000378:metabolism; D021381:Protein Transport / Q000528:radiation effects; D053218:Receptors, Death Domain / Q000378:metabolism; D015398:Signal Transduction / Q000528:radiation effects; D013347:Subcellular Fractions / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014466:Ultraviolet Rays; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D002457:Cell Extracts; D004268:DNA-Binding Proteins; C102997:Msh6 protein, mouse; D053218:Receptors, Death Domain; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; C090208:Casp2 protein, mouse; D053143:Caspase 2; D053453:Caspase 9; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein