Unanswered questions abound around how age creeps up upon us and our cells. Our current understanding of cellular aging rests upon the uncapping of the repetitive, non-protein-coding extremities of our linear chromosomes called telomeres. Uncapped and unprotected, the free ends of chromosomal DNA are vulnerable to DNA-chopping exonucleases and the ever-vigilant recombination machinery that seals free DNA ends. This telomeric uncapping triggers a continuous DNA Damage Response (DDR) that induces a stable state of cellular senescence accompanied by a complete suspension of cell division.
A team of cancer scientists led by Francis Rodier, PhD, a professor at the University of Montréal, has updated the current model of cellular senescence by providing evidence that the aging-related arrest of DNA replication is caused by irreversible damage to the genome rather than simply by an erosion of telomeres. The team also showed that this stable stage is preceded by an unstable transient stage when the cell continues to divide despite uncapped telomeres.
“What’s most surprising is that, before really entering senescence, the cells divide one last time,” said Rodier. “In fact, the cell division caused by telomere dysfunction is so unstable that it ends up creating genetic defects. Contrary to what was believed, senescent cells have an abnormal genome. That’s what we show in our study.”
The study is reported in an article in the journal Nucleic Acids Research, titled, “Homologous recombination-mediated irreversible genome damage underlies telomere-induced senescence.”
These findings improve upon the widely accepted scientific model of cellular aging that holds, telomeric ends erode with each cell division and trigger an arrest of cell division once they get too short, preventing further damage of the DNA code.
The arrest of cell division related to cellular aging prevents cells with unstable genomes from multiplying and is a key mechanism in suppressing cancer. Aged, nondividing cells however continue to play an array of biological roles and their accumulation in tissues over time compromises tissue functions, linking cellular aging to organismal aging and cancer.
The traditional model of cellular aging is unable to reconcile all observations in the aging cell. It cannot help in determining the cellular threshold for the number of dysfunctional telomeres that causes cells to stop dividing due to persistent DNA damage response signaling. Also unknown is why telomeric uncapping which is considered a DNA double stranded break does not stably activate the “guardian of the genome,” a tumor suppressor protein called p53.
“In this study, we examined whether normal human cells could tolerate telomere uncapping and showed that p53 wild-type diploid cells reacted but rapidly adapted to telomere uncapping,” the authors noted.
The new multistep model for entry into telomere-mediated senescence presented in the current study reconciles observations of senescence-associated genomic instability with observations that telomere breaks are largely irreparable and that cells can tolerate telomere-induced DNA damage foci (TIF) during an unstable “pre-senescent” state.
“We demonstrate that replicative senescence, a tumor suppressor mechanism and guardian of genome stability, sometimes requires genomic instability to initiate its own action,” the authors said.
This updated model offers a new basis for stress- or age-associated genome damage and indicates, cells that escape telomere-mediated senescence harbor irreparable genome damage. The model also suggests that strategies targeted at repairing telomeres in pre-senescent cells could eradicate telomere-induced DNA damage foci and low-level DNA damage response while preventing further irreversible damage to the genome.
“Genetically, we were able to reproduce the phenomenon of cellular aging in the laboratory and ensured that all the telomeres of a population of cells became dysfunctional,” said PhD student Marc-Alexandre Olivier, co-first author of the study with former colleague Sabrina Ghadaouia, PhD, currently pursuing postdoctoral studies in England. “With our equipment, we then observed in real time what was happening inside each single cell.”
Although the current model accepts that telomeric uncapping triggers a telomeric DNA damage response that leads to senescence, the authors showed entry into senescence involves DNA repair mechanisms and a multistep relationship between irreversible telomeric and non-telomeric DNA damage, which control a transient unstable state and a stable state where cell division is arrested.
“In contrast to previous senescence models, we suggest that irreversible genomic instability, rather than TIF [telomere-induced DNA damage foci], is required to establish replicative senescence in normal cells,” the authors wrote.
The study opens new research opportunities into cancer and aging. For example, could telomeres be repaired before cells reach a stable senescent phase when cell division stops? If possible, this would stall genomic instability and prevent cellular aging. These investigations could pave the way for potential therapeutic approaches to cellular rejuvenation.