mTOR regulates the expression of DNA damage response enzymes in long-lived Snell dwarf, GHRKO, and PAPPA-KO mice

Aging Cell. 2017 Feb;16(1):52-60. doi: 10.1111/acel.12525. Epub 2016 Sep 13.

Abstract

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.

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

MeSH terms

  • Animals
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • DNA Damage*
  • DNA Modification Methylases / genetics*
  • DNA Modification Methylases / metabolism
  • DNA Repair Enzymes / genetics*
  • DNA Repair Enzymes / metabolism
  • Down-Regulation / drug effects
  • Dwarfism / metabolism*
  • Female
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Liver / drug effects
  • Liver / metabolism
  • Longevity*
  • Male
  • Mice, Knockout
  • Models, Biological
  • Pregnancy-Associated Plasma Protein-A / deficiency*
  • Pregnancy-Associated Plasma Protein-A / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, CCR4 / metabolism
  • Receptors, Somatotropin / deficiency*
  • Receptors, Somatotropin / metabolism
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / metabolism*
  • Transcription Factors / metabolism
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism

Substances

  • CNOT3 protein, mouse
  • Cell Cycle Proteins
  • Intracellular Signaling Peptides and Proteins
  • N-myc downstream-regulated gene 1 protein
  • RNA, Messenger
  • Receptors, CCR4
  • Receptors, Somatotropin
  • Transcription Factors
  • Tumor Suppressor Proteins
  • DNA Modification Methylases
  • MGMT protein, mouse
  • TOR Serine-Threonine Kinases
  • Pregnancy-Associated Plasma Protein-A
  • DNA Repair Enzymes
  • Sirolimus