The circadian gene NPAS2, a putative tumor suppressor, is involved in DNA damage response

Mol Cancer Res. 2008 Sep;6(9):1461-8. doi: 10.1158/1541-7786.MCR-07-2094.

Abstract

Apart from regulating sleep and wakefulness, the circadian system may play an important role in other biological processes, including pathways involved in tumorigenesis. Two genetic association studies recently conducted by our lab have shown that a missense mutation in neuronal PAS domain protein 2 (NPAS2), a core circadian gene and transcriptional regulator, is significantly associated with risk of breast cancer and non-Hodgkin's lymphoma. Our current functional analyses provide the first in vitro evidence further demonstrating that cells with RNA interference-mediated depletion of NPAS2 fail to exhibit the expected cell cycle delay in response to mutagen treatment. DNA repair capacity, as measured by the comet assay, is also impaired. Moreover, a pathway-based PCR expression array of genes important for DNA damage signaling showed that knockdown of NPAS2 significantly represses the expression of several cell cycle and DNA repair genes. Thus, NPAS2 may play a role in tumorigenesis by affecting expression of cancer-related genes and could be considered a novel tumor suppressor.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Apoptosis / physiology
  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Blotting, Western
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Cycle / physiology*
  • Cell Survival / physiology
  • Circadian Rhythm
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Comet Assay
  • DNA Damage*
  • DNA Repair
  • Flow Cytometry
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Nerve Tissue Proteins / genetics*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription, Genetic
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • NPAS2 protein, human
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • RNA, Messenger
  • Tumor Suppressor Proteins