Abstract 4679: Investigating the role of cryptochrome 2 in human cancer

Abstract

Abstract Through numerous epidemiological studies, The World Health Organization (WHO) deemed disruption of circadian rhythms a probable carcinogen. Circadian rhythms regulate many physiological and cellular processes, while maintaining a ~24hr period. The molecular mechanisms by which disrupted circadian rhythms promote tumorigenesis remain unclear. Recently, our lab found that Cryptochrome 2 (CRY2) acts as an adapter to recruit c-MYC to the E3 ligase complex SKP-CULLIN-FBXL3 (SCFFBXL3) to promote degradation of c-MYC, a known proto-oncogene transcription factor. We identified five recurrent CRY2 mutations (CRY2 D347H, S436R, R460C, D467N and S532L) in a variety of human cancers from The Cancer Genome Atlas (TCGA) (referred to as CRY2 TCGA mutations). We hypothesized that these mutations may disrupt the interactions between CRY2, FBXL3, and c-MYC and thereby promote c-MYC accumulation. We performed several biochemical and functional assays in parallel to investigate the impact of these mutations on CRY2 activities. While three of the mutants tested reduce the association of CRY2 with FBXL3 as expected, we unexpectedly found that one of the CRY2 TCGA mutants abolishes interaction between CRY2, CLOCK, and BMAL1 without affecting its ability to interact with FBXL3 or c-MYC. Thus, this mutation prevents the normal function of CRY2 within the circadian clock and affects two-dimensional colony formation, which could impact cellular transformation as well. Citation Format: Alanna Chan, Katja Lamia. Investigating the role of cryptochrome 2 in human cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4679.