Two sides of the Myc-induced DNA damage response: from tumor suppression to tumor maintenance

c-MYC (henceforth MYC) is an immediate-early serum response gene essential for embryonic development, cellular proliferation and survival, and a cellular proto-oncogene that is frequently up-regulated in cancer. The Myc protein is a basic Helix-Loop-Helix Leucine Zipper (bHLHZip) transcription factor, which forms transcriptionally active dimers with another bHLHZip protein called Max [1,2]. Dimerization with Max endows Myc with sequence specific DNA binding ability, preferentially to sites containing the E-box sequence CACGTG. The transactivation properties of this complex are carried out by the N-terminal portion of Myc [3]. Myc is a multifunctional transcription factor able to regulate cell cycle, growth, metabolism, differentiation, apoptosis, transformation, genomic instability, and angiogenesis. Recently, transcription independent functions of Myc have been proposed particularly concerning the role of Myc in regulating pre-replication complexes assembly onto DNA replication origins [4]. While low Myc levels are necessary and sufficient for cellular viability and proliferation, pathological activation of this proto-oncogene has been linked to over-expression and gain of function mutations [5-7]. Pathological over-expression is frequently achieved by transcriptional up-regulation due to chromosomal translocation leading to promoter rearrangement [8-12], gene amplification [13,14] or by virus mediated insertional mutagenesis [15,16]. In prostate and breast cancers, a significant fraction of tumors demonstrate amplification of an otherwise unrearranged c-MYC locus (Pietilainen et al., 1995; Bubendorf et al., 1999; Sato et al., 1999; Naidu et al., 2002). In contrast, the Myc mRNA and protein over-expression that is observed in 70-80% of colon carcinomas (Smith and Goh, 1996) results from aberrant transcriptional control of the MYC locus involving mutations in APC-b-catenin-TCF-4 pathway members (Barker et al., 2000). Similarly, in Human acute T-cell lymphoblastic le