Early SRC activation skews cell fate from apoptosis to senescence

Area of Science:

• Cellular biology
• Molecular biology
• Genetics

Background:

• Cells respond to DNA damage through adaptive programs, leading to either apoptosis or senescence.
• Identifying factors that dictate this cell fate decision is crucial for understanding cellular responses to genotoxic stress.

Purpose of the Study:

• To systematically identify key factors, specifically kinases, that drive the dichotomous cell fate decision between apoptosis and senescence following DNA damage.
• To elucidate the role of SRC kinase in this decision-making process.

Main Methods:

• Human IMR-90 fibroblasts were exposed to increasing doses of the genotoxin etoposide.
• Activation of SRC, p38, and p53 pathways were analyzed in response to varying levels of DNA damage.
• Pharmacologic inhibition of SRC was tested in mice exposed to DNA damage.

Main Results:

• SRC kinase was activated by low, but not high, levels of etoposide-induced DNA damage.
• Low DNA damage with SRC activation promoted senescence-related proteins via p38 activation and suppressed apoptosis via p53 repression.
• High DNA damage without SRC activation led to p53 elevation, p38 inhibition, and subsequent apoptosis.
• Inhibition of SRC in mice prevented the accumulation of senescent cells.

Conclusions:

• SRC acts as a critical determinant of cell fate following DNA damage, with its activation state dictating the balance between senescence and apoptosis.
• Targeting SRC could be a therapeutic strategy to promote apoptosis over senescence in tissues, potentially improving health outcomes in conditions involving DNA damage.