Abstract

Telomere to mitochondria signaling prevents age-associated cancer initiation

Tobias Schmidt1, Marco R. Cosenza2, Joe Nassour3, Carly Tyer4, Scott Hickey4, Jan Korbel2, Jan Karlseder1

1Salk Institute for Biological Studies, La Jolla, CA, USA . 2Genome Biology, European Molecular Biology Laboratory, Heidelberg, Germany. 3Department of Biochemistry and Molecular Genetics, University of Colorado, Anschutz Medical Campus, Denver, CO, USA . 4Oxford Nanopore Technologies, Inc., New York, NY, USA .

Cancers arise through accumulation of genetic and epigenetic alterations allowing cells to evade telomere-based proliferative barriers and achieve immortality. One such barrier is replicative crisis, an autophagy-dependent program eliminating checkpoint-deficient cells with unstable telomeres. Cells that escape crisis exhibit cancer-relevant chromosomal aberrations, yet little is known about the molecular events regulating the onset of this tumor suppressive barrier. We discovered that crisis is executed through an intricate interplay between innate DNA and RNA sensing machineries, activated by critically short telomeres. We found that three hallmarks of aging, telomeres, mitochondria and inflammation, synergize in molecular pathways to prevent age associated cancer initiation. Furthermore, analysis of single cells during crisis and cells that escaped crisis revealed a role for genome instability in executing the crisis program. Our discoveries establish novel mechanisms for telomere-mediated tumor suppression, whereby dysfunctional telomeres activate lethal innate immune signaling to eliminate cells at risk for neoplastic transformation.