How mutations of intrinsically disordered protein regions can drive cancer

Abstract

Intrinsically disordered regions (IDRs) are important functional modules of several proteins, providing extra layers of regulation as switchable structural elements. Protein disorder has been associated with cancer, but it is unknown whether IDR mutations represent a distinct class of driver events associated with specific molecular mechanisms and system level properties, which would require dedicated targeting strategies. Based on an integrative computational approach, we identified 47 IDRs whose genetic mutations can be directly linked to cancer development. While not as common as alterations of globular domains, IDR mutations contribute to the emergence of the same cancer hallmarks through the modulation of distinct molecular mechanisms, increased interaction potential and specific functional repertoire. We demonstrate that in specific cancer subtypes, IDR mutations represent the key events driving tumorigenesis. However, treatment options for such patients are currently severely limited. We suggest targeting strategies that could enable successful therapeutic intervention for this subclass of cancer drivers, extending our options for personalized therapies.

Ancient Evolutionary Origin of Intrinsically Disordered Cancer Risk Regions

“…We used a subset of the previously identified disordered cancer risk regions [ 8 ]. These regions were identified based on genetic variations collected from the COSMIC database [ 11 ] using the method that located specific regions that are enriched in cancer mutations [ 7 ].…”

“…These regions were identified based on genetic variations collected from the COSMIC database [ 11 ] using the method that located specific regions that are enriched in cancer mutations [ 7 ]. Disorder status of these regions was verified based on experimental data collected from dedicated databases and from the literature when available, or based on consensus disorder prediction methods [ 8 ]. Mapping was not feasible for CDKN2A isoform (Tumor suppressor ARF), because it was not present in the ENSEMBL database we used in our study), hence this protein was excluded from the further analyses.…”

“…In our recent work, we systematically collected disordered regions that are directly targeted by cancer mutations and analyzed their basic functional and system level properties. [ 8 ]. While only a relatively small subset of such disordered cancer drivers was identified, their mutations can be the main driver event in certain cancer types.…”

“…These disordered regions can function in a variety of ways including post-transcriptional modification sites (PTMs), linear motifs, linkers, and larger sized functional modules typically involved in binding to macromolecular complexes. These disordered cancer drivers have a characteristic functional repertoire and increased interaction potential, and their perturbation can give rise to all ten hallmarks of cancer independently of ordered drivers [ 8 ].…”

“…In the current study, we studied the evolutionary origin of disordered cancer risk regions. For this, we used a dataset of cancer driving proteins in which cancer mutations specifically targeted intrinsically disordered regions [ 8 ]. We retrieved phylogeny data from the ENSEMBL Compara database.…”