The absence of efficient mass spectrometry-based approaches for the large-scale analysis of
protein arginine methylation has hindered the understanding of its biological role, beyond the transcriptional
regulation occurring through histone modification. In the last decade, however, several
technological advances of both the biochemical methods for methylated polypeptide enrichment and
the computational pipelines for MS data analysis have considerably boosted this research field, generating
novel insights about the extent and role of this post-translational modification.
Here, we offer an overview of state-of-the-art approaches for the high-confidence identification and
accurate quantification of protein arginine methylation by high-resolution mass spectrometry methods,
which comprise the development of both biochemical and bioinformatics methods. The further optimization
and systematic application of these analytical solutions will lead to ground-breaking discoveries
on the role of protein methylation in biological processes.