Tl. Deweese et al., MOUSE EMBRYONIC STEM-CELLS CARRYING ONE OR 2 DEFECTIVE MSH2 ALLELES RESPOND ABNORMALLY TO OXIDATIVE STRESS INFLICTED BY LOW-LEVEL RADIATION, Proceedings of the National Academy of Sciences of the United Statesof America, 95(20), 1998, pp. 11915-11920
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 expos
ed to low levels of ionizing radiation, a stress known to generate oxi
dative DNA damage. ES cells derived from mice carrying either one or t
wo disrupted Msh2 alleles displayed an increased survival following pr
otracted exposures to low-level ionizing radiation as compared with wi
ld-type ES cells. The increases in survival exhibited by ES cells defi
cient 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 radiatio
n treatment generated oxidative genome damage that manifested as an ac
cumulation of oxidized bases in genomic DNA. However, ES cells from Ms
h2(+/-) and Msh2(-/-) mice accumulated more oxidized bases as a conseq
uence of low-level radiation exposure than ES cells from Msh2(+/+) mic
e. The propensity for normal cells with mismatch repair enzyme deficie
ncies, including cells heterozygous for inactivating mismatch repair e
nzyme gene mutations, to survive promutagenic genome insults accompany
ing oxidative stresses may contribute to the increased cancer risk cha
racteristic of the hereditary nonpolyposis colorectal cancer syndrome.