Impaired function of p53R2 in Rrm2b-null mice causes severe renal failure through attenuation of dNTP pools.
p53R2, which is regulated by tumor suppressor p53, is a small subunit of ribonucleotide reductase. To determine whether it is involved in DNA repair by supplying deoxyribonucleotides (dNTPs) for resting cells in vivo, we generated a strain of mice lacking Rrm2b (encoding p53R2). These mice developed normally until they were weaned but from then on had growth retardation and early mortality. Pathological examination indicated that multiple organs had failed, and all Rrm2b-null mice died from severe renal failure by the age of 14 weeks. TUNEL staining showed a greater number of apoptotic cells in kidneys of 8-week-old Rrm2b-/- mice relative to wild-type mice. p53 was activated in kidney tissues of Rrm2b-/- mice, leading to transcriptional induction of p53 target genes. Rrm2b-/- mouse embryonic fibroblasts (MEFs) became immortal much earlier than Rrm2b+/+ MEFs. dNTP pools were severely attenuated in Rrm2b-/- MEFs under oxidative stress. Rrm2b deficiency caused higher rates of spontaneous mutation in the kidneys of Rrm2b-/- mice. Our results suggest that p53R2 has a pivotal role in maintaining dNTP levels for repair of DNA in resting cells. Impairment of this pathway may enhance spontaneous mutation frequency and activate p53-dependent apoptotic pathway(s) in vivo, causing severe renal failure, growth retardation and early mortality.
Kimura
Takashi
T
Human Genome Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Takeda
Satoshi
S
Sagiya
Yoji
Y
Gotoh
Mitsukazu
M
Nakamura
Yusuke
Y
Arakawa
Hirofumi
H
D000818:Animals; D017209:Apoptosis; D018797:Cell Cycle Proteins; D004260:DNA Repair; D003854:Deoxyribonucleotides / Q000378:metabolism*; D005260:Female; D016158:Genes, p53; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009102:Multiple Organ Failure / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D018384:Oxidative Stress; D012264:Ribonucleotide Reductases / Q000172:deficiency* / Q000235:genetics*
D018797:Cell Cycle Proteins; D003854:Deoxyribonucleotides; D012264:Ribonucleotide Reductases; C486561:Rrm2b protein, mouse