Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation

Area of Science:

• Molecular Biology
• Cell Biology
• Genetics

Background:

• The DNA-damage response (DDR) halts cell-cycle progression until DNA is repaired.
• Persistent DDR is linked to DNA-damage-induced cellular senescence.
• The molecular mechanisms differentiating transient from persistent DDR remain unclear.

Purpose of the Study:

• To investigate the molecular basis of persistent DNA-damage response (DDR).
• To determine the role of telomeric DNA in persistent DDR and cellular senescence.

Main Methods:

• Induction of DNA damage in cultured cells and mammalian tissues.
• Analysis of DDR marker localization, particularly at telomeres.
• Investigating the effect of telomeric DNA structure and factors (e.g., TRF2) on DDR persistence.
• Assessing DDR in terminally differentiated primate tissues.

Main Results:

• A significant portion of induced persistent DDR markers localize to telomeric DNA in cells and tissues.
• A double-strand break near telomeric sequences in yeast shows impaired repair and reduced DNA ligase 4 recruitment.
• Ectopic TRF2 near a double-strand break in mammalian cells causes persistent DDR.
• Linear telomeric DNA, unlike circular or scrambled DNA, induces a prolonged checkpoint.
• DDR markers accumulate at telomeres in aged primate tissues, irrespective of telomere length.

Conclusions:

• Telomeric DNA, particularly in its linear form, plays a critical role in mediating persistent DNA-damage response.
• Damaged telomeric DNA may be irreparable, leading to sustained DDR and cellular senescence.
• This mechanism contributes to aging and tissue senescence.