DDR-mediated crosstalk between DNA-damaged cells and their microenvironment

Area of Science:

• Cell Biology
• Molecular Biology
• Cancer Research

Background:

• The DNA damage response (DDR) is crucial for sensing and repairing DNA breaks, preventing genome instability and cancer.
• DDR traditionally focuses on cell-autonomous effects like DNA repair and cell cycle arrest.
• Emerging evidence highlights DDR's role in intercellular communication.

Purpose of the Study:

• To explore the paracrine functions of the DDR signaling cascade.
• To discuss the role of extracellular DDR signals in the tumor microenvironment.
• To highlight rapid and late DDR-mediated extracellular alarm signals.

Main Methods:

• Review and discussion of existing literature on DDR signaling.
• Analysis of cell-autonomous and paracrine DDR mechanisms.
• Categorization of extracellular DDR signals into rapid and late waves.

Main Results:

• DDR signaling extends beyond the damaged cell, influencing surrounding cells and the microenvironment.
• Extracellular DDR signals can promote tissue repair and modulate local immune responses.
• Two distinct temporal waves of extracellular DDR signals exist: rapid bystander effects and delayed senescence-associated secretory phenotypes.

Conclusions:

• The paracrine DDR signaling is a critical, yet underappreciated, aspect of cancer biology.
• Targeting extracellular DDR signals presents a promising avenue for novel cancer therapeutics.
• Understanding these intercellular DDR signals is key to harnessing their full therapeutic potential.