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 the c-MYC (MYC) protein is deregulated in >50% of human cancers, the role, regulation and structural features of MYC have been well-studied. By contrast, the L-MYC protein has been relatively understudied as historically, oncogenic deregulation was evident only in a subset of small cell lung carcinomas (SCLCs). However, with recent deep genomic analyses of primary patient samples, L-MYC has been shown to be deregulated in numerous human cancers. With this revelation it is important to understand how the L-MYC protein compares to MYC at the structural level, particularly for the development of broad-spectrum inhibitors of the MYC family. Here we first show that L-MYC expression is anti-correlated with MYC expression and is elevated in several primary patient tumor samples compared to normal, providing further evidence for L-MYC as a driver oncoprotein in primary human cancers. Next, we provide new insights into the biophysical features of an N-terminal region within the transactivation domain of L-MYC, which harbors two regions conserved amongst the MYC family: MYC box 0 (MB0) and MYC box I (MBI). NMR spectroscopy of residues 1-80 of L-MYC confirms that, similar to MYC, it is largely intrinsically disordered and interacts with the known MYC MB0-interacting protein, PNUTS ( P hosphatase 1 NU clear T argeting S ubunit). On the other hand, L-MYC does not interact with the MYC MB1-interacting protein Bin1 (Bridging integrator 1), suggesting a potential mechanism by which L-MYC evades this tumor suppressor. Together, these results further substantiate the oncogenic role of L-MYC in human cancer and deeply enhance our understanding of the biophysical nature of L-MYC to better inform strategies for the development of anti-cancer therapeutics targeting the MYC family of oncoproteins.