Structure and function of the L-MYC N-terminus impacts strategies to inhibit the MYC family of oncoproteins

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.