The role of p38 MAPK pathway in p53 compromised state and telomere mediated DNA damage response

Area of Science:

• Genetics
• Molecular Biology
• Cellular Biology

Background:

• Maintaining genome stability relies on a balance between DNA damage response and repair.
• The p53 protein is crucial for cell cycle regulation and tumor suppression, but its compromised function in many cancers necessitates alternative pathways.
• Genotoxic stress from lifestyle and environmental factors causes chronic DNA damage, impacting genome homeostasis.

Purpose of the Study:

• To review the activation of the p38 MAPK signaling pathway in response to genotoxic stress and DNA damage, particularly in the context of compromised p53 function.
• To explore the crosstalk between the p38 MAPK pathway, ATM, and the telomere shelterin complex in DNA damage response.
• To highlight the potential of p38 MAPK as a therapeutic target in p53-mutated cancers and other diseases.

Main Methods:

• Literature review focusing on DNA damage response pathways.
• Analysis of signaling cascades involving p53, p38 MAPK, ATM, and telomere shelterin complex.
• Examination of evidence for p38 MAPK activation in response to genotoxic stress and its interaction with DNA repair mechanisms.

Main Results:

• The p38 MAPK pathway is activated by various cellular stresses, including DNA damage.
• Evidence suggests a crosstalk between p38 MAPK, ATM, and the telomere shelterin complex, particularly when telomeres are dysfunctional.
• p38 MAPK activation can occur independently of functional p53, suggesting a compensatory role in DNA damage response.

Conclusions:

• The p38 MAPK pathway plays a significant role in DNA damage response, especially when p53 function is compromised.
• The interaction between p38 MAPK, ATM, and shelterin complex components is critical for maintaining genomic integrity.
• Targeting the p38 MAPK pathway presents a promising therapeutic strategy for treating cancers with mutated p53 and other related diseases.