Overexpression of Cu/Zn superoxide dismutase is lethal for mice lacking double-strand break repair.
The non-homologous DNA end joining (NHEJ) pathway is a major double-strand DNA break repair pathway in cells of multicellular eukaryotes. Ku is a heterodimeric protein consisting of Ku70 and Ku86, and it is thought to be the first component to bind to a broken double-strand DNA end. Mice lacking Ku86 show features of premature aging, live about 6-12 months, and show a characteristic loss of neurons in the central nervous system during development. Cells from mice lacking Ku have increased numbers of chromosome breaks, a significant fraction of which are caused by oxidative metabolism. Overexpression of the cytoplasmic Cu/Zn superoxide dismutase (SOD1) from a transgene is known to increase the number of chromosome breaks in primary cells (presumably by increasing reactive oxygen species). Here we show that SOD1 overexpression in a Ku86-/- mouse results in embryonic lethality. This striking effect is, however, subject to a strain-specific modifier. Genome-wide marker analysis is most consistent with the modifier being on mouse chromosome 13. Analysis of 10 markers on chromosome 13 suggests that the modifier is within the same region as a modifier of the murine amyotropic lateral sclerosis (ALS) phenotype when it is caused by overexpression of a mutant form of SOD1. Based on these results, we propose a model in which oxidative metabolism causes chromosome breaks, leading to neuronal death; and this neuronal death may account for that seen in NHEJ mutant animals and in mammals with SOD1-mediated ALS.
Karanjawala
Zarir E
ZE
Department of Pathology, USC Norris Comprehensive Cancer Center, Rm 5428, Keck School of Medicine, University of Southern California, 1441 Eastlake Ave, MC9176, Los Angeles, CA 90089-9176, USA.
Hsieh
Chih-Lin
CL
Lieber
Michael R
MR
D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics* / Q000378:metabolism; D002874:Chromosome Mapping; D004265:DNA Helicases; D004260:DNA Repair / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D018628:Gene Dosage; D005804:Genes, Lethal; D000072200:Ku Autoantigen; D051379:Mice; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics*
D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D013482:Superoxide Dismutase; D004265:DNA Helicases; C106893:XRCC5 protein, human; C000606512:Xrcc5 protein, mouse; C000606509:Xrcc6 protein, human; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen