Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Gene Section Mini Review

DRAM (damage-regulated autophagy modulator) Michael J Spinella Department of Pharmacology, Dartmouth Medical School, 7650 Remsen, Hanover NH 03755, USA (MJS)

Published in Atlas Database: April 2008 Online updated version: http://AtlasGeneticsOncology.org/Genes/DRAMID44093ch12q23.html DOI: 10.4267/2042/44422 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2009 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Expression No expression data for endogenous DRAM is available Other names: FLJ11259 at the level. Location: 12q23.2 Local order: Cen-SYCP3-GNPTAB-DRAM- Localisation LOC100129880-CCDC53-Tel. Overexpressed and tagged DRAM appears to localize to the lysosome. Localization of endo-genous DRAM DNA/RNA has not been reported. Description Function The precise function of DRAM is unknown. The first The encompasses 46.3 Kb of DNA and contains 7 paper reporting a biologic activity for DRAM was in exons. All exons are coding with exon 1 and exon 7 2006. There is strong evidence from multiple sources containing additional noncoding sequences at their 5' that DRAM (FLJ11259) is a direct p53 target gene and and 3' ends, respectively. is induced in response to DNA damage. This includes Transcription global p53-induced gene expression and global p53 The major transcript is 3553 bp. An alternative, in- ChIP-PET studies. DRAM is a mediator of autophagy frame spliced variant has been described that skips and is required for p53-induced apoptosis in response exon 4 and exon 5. Significance of this transcript is not to DNA damage. However, DRAM has minimal effects known. DRAM mRNA is induced in a p53-dependent alone on cell growth or apoptosis. DRAM mRNA is manner after cellular or genotoxic stress. Two downregulated in some tumors compared to normal. alternative functional p53 consensus enhancer elements Overall evidence suggests DRAM may be a tumor have been described. DRAM is also induced by p73. suppressor downstream of p53. However, whether the DRAM mRNA appears to be widely expressed in role of DRAM in autophagy is positive or negative and various tissues and cell types. DRAM mRNA is whether DRAM mediates cell death or survival in reported to be decreased in various tumor types pathologic and physiologic settings may be complex compared to normal tissue. and context dependent. Pseudogene Homology 4 (LOC727709). DRAM is highly conserved in higher metazoans including C. elegans, Drosophila, and Zebrafish. Protein DRAM shares no homology with any of known function. DRAM has no known functional Description domains. Human DRAM shares significant homology DRAM consists of 238 amino acids. It is predicted to with other 6 transmembrane proteins of unknown have 6 transmembrane regions. DRAM is a lysosomal function, including TMEM77, TMEM150 (TM6P1), protein that is required for induction of autophagy by and FLJ12993. TM6P1 was cloned by subtractive the p53 pathway. hybridization as induced in starved rat liver. Nutrient

Atlas Genet Cytogenet Oncol Haematol. 2009; 13(3) 194 DRAM (damage-regulated autophagy modulator) Spinella MJ

starvation is a major physiologic inducer of autophagy. Crighton D, Wilkinson S, O'Prey J, Syed N, Smith P, Harrison PR, Gasco M, Garrone O, Crook T, Ryan KM. DRAM, a p53- induced modulator of autophagy, is critical for apoptosis. Cell. Mutations 2006 Jul 14;126(1):121-34 Note Green DR, Chipuk JE. p53 and metabolism: Inside the TIGAR. Have not been described. Cell. 2006 Jul 14;126(1):30-2 Wei CL, Wu Q, Vega VB, Chiu KP, Ng P, Zhang T, Shahab A, Implicated in Yong HC, Fu Y, Weng Z, Liu J, Zhao XD, Chew JL, Lee YL, Kuznetsov VA, Sung WK, Miller LD, Lim B, Liu ET, Yu Q, Ng HH, Ruan Y. A global map of p53 transcription-factor binding Autophagy sites in the . Cell. 2006 Jan 13;124(1):207-19 Note Crighton D, O'Prey J, Bell HS, Ryan KM. p73 regulates DRAM- DRAM may be involved in diseases associated with independent autophagy that does not contribute to deregulation of autophagy. DRAM may link p53 and programmed cell death. Cell Death Differ. 2007 cancer suppression/ treatment to autophagy. Jun;14(6):1071-9 Crighton D, Wilkinson S, Ryan KM. DRAM links autophagy to References p53 and programmed cell death. Autophagy. 2007 Jan- Feb;3(1):72-4 Zhang J, D'Ercole AJ, Underwood LE. Identification of a new Kerley-Hamilton JS, Pike AM, Hutchinson JA, Freemantle SJ, gene (rat TM6P1) encoding a fasting-inducible, integral Spinella MJ. The direct p53 target gene, FLJ11259/DRAM, is a membrane protein with six transmembrane domains. Biochim member of a novel family of transmembrane proteins. Biochim Biophys Acta. 2000 Jun 21;1492(1):280-4 Biophys Acta. 2007 Apr;1769(4):209-19 Kerley-Hamilton JS, Pike AM, Li N, DiRenzo J, Spinella MJ. A p53-dominant transcriptional response to cisplatin in testicular This article should be referenced as such: germ cell tumor-derived human embryonal carcinoma. Oncogene. 2005 Sep 8;24(40):6090-100 Spinella MJ. DRAM (damage-regulated autophagy modulator). Atlas Genet Cytogenet Oncol Haematol. 2009; 13(3):194-195.

Atlas Genet Cytogenet Oncol Haematol. 2009; 13(3) 195