Telomere-to-mitochondria signalling by ZBP1 mediates replicative crisis

Area of Science:

• Cellular biology
• Immunology
• Cancer research

Background:

• Cancers develop from genetic/epigenetic changes allowing cells to bypass telomere limits and gain immortality.
• Replicative crisis is an autophagy-dependent process eliminating cells with unstable telomeres and chromosomal issues.
• The molecular triggers of this crucial tumor-suppressive barrier remain largely unknown.

Purpose of the Study:

• To identify molecular regulators of the replicative crisis program.
• To elucidate the role of Z-DNA binding protein 1 (ZBP1) in telomere-mediated tumor suppression.

Main Methods:

• Investigated Z-DNA binding protein 1 (ZBP1) as a regulator of replicative crisis.
• Examined the induction of a crisis-associated ZBP1 isoform via the cGAS-STING pathway.
• Assessed ZBP1 activation by telomeric-repeat-containing RNA (TERRA) and its localization to mitochondria.
• Studied ZBP1 oligomerization and activation of mitochondrial antiviral-signalling protein (MAVS).

Main Results:

• Identified ZBP1 as a key regulator of the replicative crisis.
• A ZBP1 isoform is induced by cGAS-STING but requires TERRA from dysfunctional telomeres for full activation.
• TERRA-bound ZBP1 forms filaments on mitochondria, activating MAVS and initiating an interferon response.
• ZBP1 oligomerization acts as a signal amplification mechanism for the interferon response.

Conclusions:

• Dysfunctional telomeres activate innate immune responses through mitochondrial TERRA-ZBP1 complexes.
• This mechanism eliminates cells with neoplastic potential, revealing a telomere-mediated tumor suppression pathway.
• ZBP1's role in sensing telomere dysfunction and initiating immune responses is crucial for tumor suppression.