The Circadian Gene NPAS2, a Putative Tumor Suppressor, Is Involved in DNA Damage Response

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.

A polymorphic GGC repeat in the NPAS2 gene and its association with melanoma

“…The NPAS2 gene, which is expressed both in the brain and periphery, 13 is known to be involved in DNA damage response mechanisms and is recognized a potential risk biomarker in human malignancies. 10,16,18 Since published data strongly support the involvement of the NPAS2 gene in tumorigenesis, we undertook a study to investigate the potential association of melanoma with the genetic status of the NPAS2 gene promoter. Indeed, a variant NPAS2 promoter sequence, e.g.…”

“…However, it is also expressed in some peripheral organs such as liver and skin. 10,11 The NPAS2 gene encodes a member of the bHLH-PAS class of transcription factors and is composed of 21 exons. The first exon, however, is a not-coding exon, and the length of the main transcript is about 4007 bp.…”

“…10 Specifically, the BMAL1/NPAS2 heterodimer negatively regulates the expression of the c-Myc oncogene. 15 Moreover, NPAS2 influences the activity of other genes involved in tumorigenesis.…”

Lack of Association of the NPAS2 Gene Ala394Thr Polymorphism (rs2305160:G>A) with Risk of Chronic Lymphocytic Leukemia

“…NPAS2 may not only directly regulate other genes in the circadian regulatory system (Asher and Schibler, 2006;DeBruyne et al, 2007) but genes involved in cancerrelated biological pathways are also influenced by it (Hoffman et al, 2008;Yi et al, 2009). This could explain the observed functional effect of NPAS2 knockdown on cell cycle progression and DNA repair capacity, as well as the epidemiologic evidence indicating an association between polymorphisms in NPAS2 and cancer risk (Zhu et al, 2007;.…”

“…Now recent studies describe NPAS2 as a putative tumor suppressor playing an important role in DNA damage response, cell cycle control and apoptosis by activating different downstream genes (Chen-Goodspeed and Lee, 2007;Hoffman et al, 2008;Yi et al, 2009). Similarly, emerging data have revealed the role of NPAS2 as a risk biomarker in human cancers as significant associations were found between a missense polymorphism (SNP rs2305160:G>A, Ala394Thr) in NPAS2 and risk of breast cancer , prostate cancer (Chu et al, 2007) and non-Hodgkin's lymphoma (Zhu et al, 2007).…”