Mouse embryonic stem cells carrying one or two defective Msh2 alleles respond abnormally to oxidative stress inflicted by low-level radiation.
Chronic oxidative stress may play a critical role in the pathogenesis of many human cancers. Here, we report that mouse embryonic stem (ES) cells deficient in DNA mismatch repair responded abnormally when exposed to low levels of ionizing radiation, a stress known to generate oxidative DNA damage. ES cells derived from mice carrying either one or two disrupted Msh2 alleles displayed an increased survival following protracted exposures to low-level ionizing radiation as compared with wild-type ES cells. The increases in survival exhibited by ES cells deficient in DNA mismatch repair appeared to have resulted from a failure to efficiently execute cell death (apoptosis) in response to radiation exposure. For each of the ES cell types, prolonged low-level radiation treatment generated oxidative genome damage that manifested as an accumulation of oxidized bases in genomic DNA. However, ES cells from Msh2(+/-) and Msh2(-/-) mice accumulated more oxidized bases as a consequence of low-level radiation exposure than ES cells from Msh2(+/+) mice. The propensity for normal cells with mismatch repair enzyme deficiencies, including cells heterozygous for inactivating mismatch repair enzyme gene mutations, to survive promutagenic genome insults accompanying oxidative stresses may contribute to the increased cancer risk characteristic of the hereditary nonpolyposis colorectal cancer syndrome.
DeWeese
T L
TL
The Oncology Center, Johns Hopkins University School of Medicine, Marburg 411, 600 North Wolfe Street, Baltimore, MD 21287, USA.
Shipman
J M
JM
Larrier
N A
NA
Buckley
N M
NM
Kidd
L R
LR
Groopman
J D
JD
Cutler
R G
RG
te Riele
H
H
Nelson
W G
WG
D000483:Alleles; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D002460:Cell Line; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000209:etiology / Q000235:genetics; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins; D006579:Heterozygote; D006801:Humans; D051379:Mice; D051718:MutS Homolog 2 Protein; D009154:Mutation; D018384:Oxidative Stress / Q000235:genetics / Q000528:radiation effects; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D013866:Thioguanine / Q000494:pharmacology
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein; D013866:Thioguanine