Rhythmic serotonin N-acetyltransferase mRNA degradation is essential for the maintenance of its circadian oscillation

Mol Cell Biol. 2005 Apr;25(8):3232-46. doi: 10.1128/MCB.25.8.3232-3246.2005.

Abstract

Serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase [AANAT]) is the key enzyme in melatonin synthesis regulated by circadian rhythm. To date, our understanding of the oscillatory mechanism of melatonin has been limited to autoregulatory transcriptional and posttranslational regulations of AANAT mRNA. In this study, we identify three proteins from pineal glands that associate with cis-acting elements within species-specific AANAT 3' untranslated regions to mediate mRNA degradation. These proteins include heterogeneous nuclear ribonucleoprotein R (hnRNP R), hnRNP Q, and hnRNP L. Their RNA-destabilizing function was determined by RNA interference and overexpression approaches. Expression patterns of these factors in pineal glands display robust circadian rhythm. The enhanced levels detected after midnight correlate with an abrupt decline in AANAT mRNA level. A mathematical model for the AANAT mRNA profile and its experimental evidence with rat pinealocytes indicates that rhythmic AANAT mRNA degradation mediated by hnRNP R, hnRNP Q, and hnRNP L is a key process in the regulation of its circadian oscillation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / metabolism
  • Animals
  • Arylalkylamine N-Acetyltransferase / genetics*
  • Arylalkylamine N-Acetyltransferase / metabolism
  • Base Sequence
  • Circadian Rhythm / genetics
  • Circadian Rhythm / physiology*
  • Heterogeneous-Nuclear Ribonucleoproteins / genetics
  • Heterogeneous-Nuclear Ribonucleoproteins / metabolism
  • Heterogeneous-Nuclear Ribonucleoproteins / physiology*
  • Molecular Sequence Data
  • Pineal Gland / metabolism
  • RNA Stability
  • RNA, Messenger / metabolism*
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / pharmacology
  • RNA-Binding Proteins / metabolism
  • RNA-Binding Proteins / physiology
  • Rats

Substances

  • 3' Untranslated Regions
  • Heterogeneous-Nuclear Ribonucleoproteins
  • RNA, Messenger
  • RNA, Small Interfering
  • RNA-Binding Proteins
  • Arylalkylamine N-Acetyltransferase