Cologne Seminars on Ageing "Ataxia-telangiectasia: A demonstration of the genome stability-cancer-cell senescence-aging link"
- Date: Nov 7, 2024
- Time: 01:00 PM - 02:00 PM (Local Time Germany)
- Speaker: Yossi Shiloh
- Tel Aviv University (Israel)
- Location: MPI for Biology of Ageing
- Room: Auditorium
- Host: Ron Jachimowicz (MPI AGE)
About Yossi' s talk:
Ataxia-telangiectasia (A-T), a genome instability disorder caused by the loss of the ATM protein kinase, is characterized by tissue degeneration, cancer predisposition, and premature aging. I found early on that primary skin fibroblasts from A-T patients exhibit premature senescence in culture. Our group has recently demonstrated that culturing human A-T fibroblasts under 3% oxygen significantly extends their proliferative lifespan; however, they still undergo premature senescence, and their transcriptomic dynamics reflects replicative senescence with unique features. Extending our experiments to murine lung fibroblasts under 3% oxygen, we found that Atm-/- lung fibroblasts rapidly senesce under these conditions, whereas WT cells do not and eventually undergo transformation. Senescence in WT cells could be induced, however, through Atm gene ablation or chemical inhibition of Atm. The simultaneous loss of Atm and p53 led to senescence evasion, severe genome instability, and subsequent transformation. Our findings suggest that the rapid senescence of Atm-/- fibroblasts is driven by the interplay of the cGAS-STING, p38 MAPK, and p53 pathways, in response to persistent DNA damage, ultimately leading to the induction of interferon-α1 and downstream interferon-stimulated genes.
Finally, I present an update on our long-term follow-up of the health status of human A-T carriers. The results indicate that the ATM+/- genotype contributes to various aging-associated morbidities, particularly an increased predisposition to cancer and cardiovascular diseases, highlighting the public health implications of heterozygosity for a mutation at a single locus.