mTOR regulates the expression of DNA damage response enzymes in long-lived Snell dwarf, GHRKO, and PAPPA-KO mice.
Studies of the mTOR pathway have prompted speculation that diminished mTOR complex-1 (mTORC1) function may be involved in controlling the aging process. Our previous studies have shown diminished mTORC1 activity in tissues of three long-lived mutant mice: Snell dwarf mice, growth hormone receptor gene disrupted mice (GHRKO), and in this article, mice deficient in the pregnancy-associated protein-A (PAPPA-KO). The ways in which lower mTOR signals slow aging and age-related diseases are, however, not well characterized. Here, we show that Snell, GHKRO, and PAPPA-KO mice express high levels of two proteins involved in DNA repair, O-6-methylguanine-DNA methyltransferase (MGMT) and N-myc downstream-regulated gene 1 (NDRG1). Furthermore, we report that lowering mTOR enhances MGMT and NDRG1 protein expression via post-transcriptional mechanisms. We show that the CCR4-NOT complex, a post-transcriptional regulator of gene expression, is downstream of the mTORC1 pathway and may be responsible for the upregulation of MGMT and NDRG1 in all three varieties of long-lived mice. Our data thus suggest a novel link between DNA repair and mTOR signaling via post-transcriptional regulation involving specific alteration in the CCR4-NOT complex, whose modulation could control multiple aspects of the aging process.
Department of Molecular, Cellular, and Developmental Biology, University of Michigan College of Literature, Science and the Arts, Ann Arbor, MI, USA.
Graham
G
Dominick
Department of Molecular, Cellular, and Developmental Biology, University of Michigan College of Literature, Science and the Arts, Ann Arbor, MI, USA.
Jacqueline
J
Bowman
Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA.
Xinna
X
Li
Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA.|University of Michigan Geriatrics Center, Ann Arbor, MI, USA.
Richard A
RA
Miller
Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA.
Gonzalo G
GG
Garcia
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage; D015254:DNA Modification Methylases / Q000235:genetics* / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004392:Dwarfism / Q000378:metabolism*; D005260:Female; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008136:Longevity; D008297:Male; D018345:Mice, Knockout; D008954:Models, Biological; D011266:Pregnancy-Associated Plasma Protein-A / Q000172:deficiency* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054398:Receptors, CCR4 / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000172:deficiency* / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D000099259:N-myc Downstream-Regulated Gene 1 Protein
D018797:Cell Cycle Proteins; D015254:DNA Modification Methylases; D045643:DNA Repair Enzymes; D047908:Intracellular Signaling Peptides and Proteins; D011266:Pregnancy-Associated Plasma Protein-A; D012333:RNA, Messenger; D054398:Receptors, CCR4; D011986:Receptors, Somatotropin; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C569362:CNOT3 protein, mouse; C528331:MGMT protein, mouse

IGF
; DNA repair; gene expression; molecular biology of aging; signal transduction