Integrative analysis of YTHDC1 phosphoproteome unveils its phosphomodulatory network linked to splicing and

Megha Shaji1, Levin John1,2, Suhail Subair1

  • 1Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), Mangalore, Karnataka, India.

Abstract

Insights

YTHDC1 protein phosphorylation is crucial for RNA splicing and cancer signaling. This study identifies key phosphosites and potential upstream kinases, offering insights into YTHDC1 regulation.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Cancer Research

Background:

  • YTH domain-containing protein 1 (YTHDC1) is a nuclear reader of m6A-modified RNA involved in mRNA processing and DNA damage.
  • The phosphoregulatory mechanisms governing YTHDC1 function are largely unknown, despite numerous detected phosphosites.

Purpose of the Study:

  • To delineate the phosphoregulatory landscape of YTHDC1.
  • To identify predominant phosphosites and their associated regulatory networks.
  • To explore the functional implications of YTHDC1 phosphorylation in cellular processes and disease.

Main Methods:

  • Integrative analysis of large-scale human phosphoproteomic datasets.
  • Ranking and identification of predominant YTHDC1 phosphosites.
  • Co-phosphorylation analysis, upstream kinase prediction, and protein-interaction network mapping.
  • Phosphomotif-based analysis to identify potential kinases.

Main Results:

  • Three predominant phosphosites (S308, S146, S424) were identified in YTHDC1.
  • Co-regulated phosphosites suggest associations with mRNA processing, splicing, and carcinogenesis.
  • Potential upstream kinases including MAPK14, CDK7, AKT1, and PAK1 were predicted.
  • The YTHDC1 phosphoregulatory network is linked to cancer-associated pathways and DNA repair inhibition.

Conclusions:

  • The study provides a framework for inferring phospho-site centric regulatory networks.
  • Predominant YTHDC1 phosphosites play a putative role in RNA splicing.
  • YTHDC1 phosphorylation is implicated in tumor-associated signaling networks.

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