The MYC family of transforming oncogenes function as regulators of gene transcription and is composed of three members, MYC, MYCN and MYCL. As c-MYC (MYC) is deregulated in 50% of human cancers, the role, regulation and structural features of MYC have been well-studied. By contrast, L-MYC has been understudied as historically, oncogenic deregulation was evident only in a subset of lung carcinomas. However, recent deep genomic analyses of primary patient samples has demonstrated that L-MYC is deregulated in numerous human cancers. With this revelation it is important to understand how L-MYC compares to MYC at the structural level, particularly for the development of broad-spectrum inhibitors of the MYC family. Here we show that L-MYC expression is elevated in several primary patient tumor samples, providing further evidence for L-MYC as a driver oncoprotein in primary human cancers. Next, we provide new biophysical insights into an N-terminal region within the L-MYC transactivation domain, which harbors two regions conserved amongst MYC proteins: MYC box 0 (MB0) and MYC box I (MBI). NMR spectroscopy of residues 1-80 of L-MYC confirms that it is largely intrinsically disordered and interacts with the known MYC-MB0 interactor, PNUTS (Phosphatase 1 NUclear Targeting Subunit). Comparatively, L-MYC does not interact with the MYC-MBI interactor and tumor suppressor Bin1 (Bridging integrator 1). Together, these results further substantiate the oncogenic role of L-MYC in human cancer and enhance our understanding of the biophysical nature of L-MYC to improve strategies for the development of anti-cancer therapeutics targeting MYC family members.
Kenney et al. (Fri,) studied this question.