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DNA damage-associated protein co-expression network in cardiomyocytes informs on tolerance to genetic variation and

Omar D Johnson1,2, Sayan Paul3, Jose A Gutierrez3

  • 1Biochemistry, Cellular and Molecular Biology Graduate Program, University of Texas Medical Branch, Galveston, Texas, USA.

Biorxiv : the Preprint Server for Biology
|August 26, 2024
PubMed

Insights

DNA damage in heart cells impacts protein networks, influencing cardiovascular disease (CVD) risk. This study reveals how DNA damage affects protein abundance and connectivity, offering new insights into CVD development.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Genetics

Background:

  • Cardiovascular disease (CVD) involves genetic and environmental factors, with DNA damage being a key molecular consequence.
  • The effect of DNA damage on cardiomyocyte protein levels and its link to CVD risk are not fully understood.

Purpose of the Study:

  • To investigate the impact of DNA damage on global cardiomyocyte protein abundance.
  • To explore the relationship between DNA damage-induced protein changes and CVD risk factors.

Main Methods:

  • Induced pluripotent stem cell-derived cardiomyocytes were treated with Doxorubicin (DOX), a DNA-damaging agent.
  • Proteomic analysis identified 4,178 proteins forming a network with 12 co-expressed modules and 403 hub proteins.
  • Correlation analysis linked DOX treatment to specific modules and proteins.

Main Results:

  • Five DOX-correlated modules were identified, representing processes like RNA processing, chromatin regulation, and metabolism.
  • DOX-correlated hub proteins were enriched for loss-of-function intolerant genes and depleted for genetically variable proteins.
  • While some CVD risk proteins (e.g., arrhythmia-related) were in DOX modules, hub proteins interacted with, rather than were, known CVD risk proteins.

Conclusions:

  • DNA damage in cardiomyocytes induces broad biological effects via protein co-expression modules relevant to CVD.
  • Protein connectivity within DNA damage-associated modules influences tolerance to genetic variation.
  • Findings suggest DNA damage impacts CVD risk through protein interaction networks rather than direct enrichment of risk proteins.

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