The Mutational Landscape of the Oncogenic MZF1 SCAN Domain in Cancer.

Mads Nygaard,Tuula Kallunki,Sanne Bergstrand-Poulsen,André Vidas Olsen,Matteo Lambrughi,Marja Jäättelä,Juan Salamanca Viloria,Fabio Rizza,Matteo Tiberti,Miriam Di Marco,Mette Vistesen,Elena Papaleo,Thilde Terkelsen,Valentina Sora

doi:10.3389/fmolb.2016.00078

Abstract

SCAN domains in zinc-finger transcription factors are crucial mediators of protein-protein interactions. Up to 240 SCAN-domain encoding genes have been identified throughout the human genome. These include cancer-related genes, such as the myeloid zinc finger 1 (MZF1), an oncogenic transcription factor involved in the progression of many solid cancers. The mechanisms by which SCAN homo- and heterodimers assemble and how they alter the transcriptional activity of zinc-finger transcription factors in cancer and other diseases remain to be investigated. Here, we provide the first description of the conformational ensemble of the MZF1 SCAN domain cross-validated against NMR experimental data, which are probes of structure and dynamics on different timescales. We investigated the protein-protein interaction network of MZF1 and how it is perturbed in different cancer types by the analyses of high-throughput proteomics and RNASeq data. Collectively, we integrated many computational approaches, ranging from simple empirical energy functions to all-atom microsecond molecular dynamics simulations and network analyses to unravel the effects of cancer-related substitutions in relation to MZF1 structure and interactions.

Highlights

Transcription factors belonging to the SCAN zinc finger family have been implicated in a number of cellular malignancies (Monaco et al, 1998; Dong et al, 2004; Yang et al, 2011; Eguchi et al, 2015; Singh et al, 2015)
To identify those interactors, which form a complex with the myeloid zinc finger 1 (MZF1) SCAN domain, we employed the PRISM approach
We integrated a plethora of different computational methods to unveil the role of MZF1 alterations in different cancer types

Summary

Introduction

Transcription factors belonging to the SCAN zinc finger family have been implicated in a number of cellular malignancies (Monaco et al, 1998; Dong et al, 2004; Yang et al, 2011; Eguchi et al, 2015; Singh et al, 2015). SCAN domains in zinc finger transcription factors are crucial mediators of protein-protein interactions (Williams et al, 1995; Sander et al, 2003; Edelstein and Collins, 2005; Noll et al, 2008) and allow SCAN zinc finger proteins to form homo- and hetero-dimers (Edelstein and Collins, 2005). The importance of dimerization for SCAN zinc finger transcriptional activity was demonstrated through two-hybrid experiments, using ZNF174. This study demonstrated that interaction between SCAN domains synergistically activated transcription (Williams et al, 1999). SCAN domains have been identified in more than 80 zinc finger genes throughout the human genome Uk/interpro/entry/IPR003309/proteins-matched?species=9606), including a number of cancer-related genes. A subset of SCAN domain only factors (SCAND), which lack the DNA binding domains, has been discovered and suggested to function as regulators of the intact SCAN zinc finger factors (Sander et al, 2003; Edelstein and Collins, 2005)

Methods

Results

Conclusion