Summary: Oxidative damage to telomeres can trigger cellular senescence. The findings could lead to the development of new therapeutics for healthy aging and to combat cancers.
Source: University of Pittsburgh
Senescent cells those that have lost the ability to divide accumulate with age and are key drivers of age-related diseases, such as cancer, dementia and cardiovascular disease.
In a new study, a team led byUniversity of PittsburghandUPMC Hillman Cancer Centerresearchers has uncovered a mechanism by which senescent, or zombie, cells develop.
Published today inNature Structural & Molecular Biology, the study shows for the first time that oxidative damage to telomeres the protective tips of chromosomes that act like plastic caps at the end of a shoelace can trigger cellular senescence. These findings could eventually point to new therapeutics that promote healthy aging or combat cancer.
Zombie cells are still alive, but they cant divide, so they dont help replenish tissues, said senior authorPatricia Opresko, Ph.D., professor of environmental and occupational health and of pharmacology and chemical biology at Pitt.
Although zombie cells dont function properly, theyre not couch potatoes they actively secrete chemicals that promote inflammation and damage neighboring cells. Our study helps answer two big questions: How do senescent cells accumulate with age, and how do telomeres contribute to that?
When a healthy human cell divides to form two identical cells, a small piece of DNA is shaved off each chromosomes tip, so that telomeres become gradually shorter with each division. However, it remains unclear whether over a persons lifetime, a cell may divide so often that its telomeres erode completely, prompting transition to a zombie-like state.
Researchers have known for decades that telomere shortening triggers senescence in lab-grown cells, but they could only hypothesize that DNA damage at telomeres could turn cells into zombies.
Until now, testing this hypothesis had not been possible because the tools used to damage DNA were non-specific, causing lesions across the whole chromosome.
Our new tool is like a molecular sniper, explained first author Ryan Barnes, Ph.D., a postdoctoral fellow inOpreskos lab. It creates oxidative damage exclusively at the telomeres.
To develop such marksman-like precision, the team used a special protein that binds exclusively to telomeres. This protein acts like a catchers mitt, grabbing hold of light-sensitive dye baseballs that the researchers tossed into the cell.
When activated with light, the dye produces DNA-damaging reactive oxygen molecules. Because the dye-catching protein binds only to telomeres, the tool creates DNA lesions specifically at chromosome tips.
Using human cells grown in a dish, the researchers found that damage at telomeres sent the cells into a zombie state after just four days much faster than the weeks or months of repeated cell divisions that it takes to induce senescence by telomere shortening in the lab.
We found a new mechanism for inducing senescent cells that is completely dependent on telomeres, explained Opresko, who also co-leads the Genome Stability Program at UPMC Hillman. These findings also solve the puzzle of why dysfunctional telomeres are not always shorter than functional ones.
Sunlight, alcohol, smoking, poor diet and other factors generate reactive oxygen molecules that damage DNA. Cells have repair pathways to patch up DNA lesions, but, according to Opresko, telomeres are exquisitely sensitive to oxidative damage. The researchers found that damage at telomeres disrupted DNA replication and induced stress signaling pathways that led to senescence.
Now that we understand this mechanism, we can start to test interventions to prevent senescence, said Barnes. For example, maybe there are ways to target antioxidants to the telomeres to protect them from oxidative damage.
The findings could also inform the development of new drugs called senolytics that home in on zombie cells and kill them.
By reducing the accumulation of zombie cells, which contribute to degenerative diseases, we might be able to promote healthspan the length of time that a person is healthy, he added.
Other authors who contributed to the study were Mariarosaria de Rosa, Ph.D., Sanjana A. Thosar, M.S., Ariana C. Detwiler, M.S., Vera Roginskaya, B.S., Bennett Van Houten, Ph.D., and Jacob Stewart-Ornstein, Ph.D., all of Pitt and UPMC, and Marcel P. Bruchez, Ph.D., Carnegie Mellon University.
Funding: This research was supported by the National Institutes of Health (F32AG067710-01, K99ES033771, R35ES030396, R01CA207342 and R01EB017268), the Glenn Foundation for Medical Research, the UPMC Hillman Cancer Center Cytometry Facility (P30CA047904) and the UPMC Hillman Cancer Center Postdoctoral Fellowship for Innovative Cancer Research.
Author: Asher JonesSource: University of PittsburghContact: Asher Jones University of PittsburghImage: The image is credited to Barnes et al., Nature Structural & Molecular Biology
Original Research: Open access.Telomeric 8-oxo-guanine drives rapid premature senescence in the absence of telomere shortening by Barnes et al. Nature Structural & Molecular Biology
Abstract
Telomeric 8-oxo-guanine drives rapid premature senescence in the absence of telomere shortening
Oxidative stress is a primary cause of cellular senescence and contributes to the etiology of numerous human diseases. Oxidative damage to telomeric DNA has been proposed to cause premature senescence by accelerating telomere shortening.
Here, we tested this model directly using a precision chemoptogenetic tool to produce the common lesion 8-oxo-guanine (8oxoG) exclusively at telomeres in human fibroblasts and epithelial cells. A single induction of telomeric 8oxoG is sufficient to trigger multiple hallmarks of p53-dependent senescence.
Telomeric 8oxoG activates ATM and ATR signaling, and enriches for markers of telomere dysfunction in replicating, but not quiescent cells. Acute 8oxoG production fails to shorten telomeres, but rather generates fragile sites and mitotic DNA synthesis at telomeres, indicative of impaired replication.
Based on our results, we propose that oxidative stress promotes rapid senescence by producing oxidative base lesions that drive replication-dependent telomere fragility and dysfunction in the absence of shortening and shelterin loss.
Continued here:
Researchers Uncover New Pathway for Accumulation of Age-Promoting 'Zombie Cells' - Neuroscience News
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