Abstract
Many proteins contain intrinsically disordered regions (IDRs) which carry out important functions without relying on a single well-defined conformation. IDRs are increasingly recognized as critical elements of regulatory networks and have been also associated with cancer. However, it is unknown whether mutations targeting IDRs represent a distinct class of driver events associated with specific molecular and system-level properties, cancer types and treatment options. Here, we used an integrative computational approach to explore the direct role of intrinsically disordered protein regions driving cancer. We showed that around 20% of cancer drivers are primarily targeted through a disordered region. These IDRs can function in multiple ways which are distinct from the functional mechanisms of ordered drivers. Disordered drivers play a central role in context-dependent interaction networks and are enriched in specific biological processes such as transcription, gene expression regulation and protein degradation. Furthermore, their modulation represents an alternative mechanism for the emergence of all known cancer hallmarks. Importantly, in certain cancer patients, mutations of disordered drivers represent key driving events. However, treatment options for such patients are currently severely limited. The presented study highlights a largely overlooked class of cancer drivers associated with specific cancer types that need novel therapeutic options.
Highlights
For the purpose of our analysis, it was necessary to use an approach that could identify cancer drivers, and the specific regions directly targeted by cancer mutations
We went beyond a simple association between intrinsically disordered regions (IDRs) and cancer by taking advantage of the avalanche of data produced by systematic analyses and large-scale sequencing projects of cancer genomes
Our work underlines the direct driver role of IDRs in cancer. It provides fundamental insights into the specific molecular mechanisms and regulatory processes altered by cancer mutations targeting IDRs, highlighting important regions that need further structural and functional characterizations
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The identification of cancer driver genes and understanding their mechanisms of action is necessary for developing efficient therapeutics [1]. Many cancer-associated genes encode proteins that are modular, containing globular domains and intrinsically disordered proteins/regions (IDPs/IDRs) [2,3,4]. IDRs can be characterized by conformational ensembles; the detailed properties of these ensembles can vary greatly from largely random-like behavior to exhibiting strong structural preferences, with the length of these segments ranging from a few residues to domain-sized segments [5,6,7]
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