title: Defining the DNA mismatch repair-dependent apoptotic pathway in primary cells: evidence for p53-independence and involvement of centrosomal caspase 2.
abstract: 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.
authors.affiliation: Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Kelly A D
authors.initials: KA
authors.lastname: Narine
authors.forename: Angela M
authors.initials: AM
authors.lastname: Keuling
authors.forename: Randi
authors.initials: R
authors.lastname: Gombos
authors.forename: Victor A
authors.initials: VA
authors.lastname: Tron
authors.forename: Susan E
authors.initials: SE
authors.lastname: Andrew
authors.forename: Leah C
authors.initials: LC
authors.lastname: Young
mesh_terms: 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
chemical_list: 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