Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion

Area of Science:

• Cellular biology
• Cancer research
• Molecular genetics

Background:

• Cellular senescence prevents cancer by halting damaged cell proliferation.
• Senescent cells secrete factors influencing tissue microenvironments, but regulatory pathways are unclear.

Purpose of the Study:

• To investigate the molecular mechanisms driving inflammatory cytokine secretion from senescent cells.
• To identify the role of DNA damage response (DDR) pathways in regulating this secretion.

Main Methods:

• Analysis of persistent chromatin lesions and DNA double-strand breaks (DSBs) in damaged human cells.
• Investigation of cytokine secretion, including interleukin-6 (IL-6), following DNA damage.
• Assessment of the requirement for DDR proteins (ATM, NBS1, CHK2) and cell-cycle regulators (p53, pRb) in cytokine secretion.
• Evaluation of IL-6 secretion in oncogene-induced senescence and in human cancers.

Main Results:

• Persistent DNA double-strand breaks (DSBs) in damaged cells initiate increased secretion of inflammatory cytokines like IL-6.
• Cytokine secretion requires sustained DNA damage signaling, mediated by DDR proteins ATM, NBS1, and CHK2, but not p53 or pRb.
• ATM is essential for IL-6 secretion in oncogene-induced senescence and in cells bypassing senescence.
• Elevated DDR activity and IL-6 are observed in human cancers, with ATM depletion reducing senescent cell-stimulated cancer cell invasiveness.

Conclusions:

• The DNA damage response (DDR) orchestrates not only cell-cycle checkpoints and DNA repair but also mediates communication from damaged cells.
• Persistent DNA damage signaling, through DDR proteins, drives inflammatory cytokine secretion, impacting tissue microenvironments and cancer progression.
• Targeting DDR-mediated communication pathways may offer novel therapeutic strategies in cancer treatment.