Regulating telomerase activity

The natural ends of chromosomes resemble broken DNA, posing a challenge in distinguishing them from intact strands. However, every cell must differentiate between the two, as the best method to safeguard the healthy end of a chromosome is also the least effective way to mend damaged DNA.

The enzyme telomerase is responsible for maintaining protective telomeres at the natural ends of chromosomes. If telomerase were to seal off a broken strand of DNA with a telomere, it would prevent further repair of that break and delete essential genes. The study published in Science describes how cells avoid such mishaps. These findings show that telomerase can indeed run amok, adding telomeres to damaged DNA, and would do so were it not for the ATR kinase, a key enzyme that responds to DNA damage.

"Telomerase is a good thing because it maintains our telomeres, but it should only be acting at the natural ends of chromosomes. It is very bad if it acts at double-stranded DNA breaks because it can lead to the loss of all genes distal to the break," says Titia de Lange, the Leon Hess professor at Rockefeller. "This detrimental aspect of telomerase is inhibited by the ATR kinase, which, among its many talents, also keeps telomerase away."

The discovery may help optimize CRISPR techniques and could inform the study of cancer.

Charles Kinzig, an MD/PhD student in the de Lange lab and colleagues first broke bits of human DNA with Cas9, the cutting component of the CRISPR gene-editing tool, and established that telomerase creates "neotelomeres" on broken DNA. Having established telomerase as driving the formation of neotelomeres, Kinzig then began interrogating various molecular pathways to determine what prevents telomerase from interfering with DNA repair under normal circumstances and found that disrupting ATR kinase signaling increases neotelomere formation and demonstrated that when ATR is activated at DNA breaks, it prevents telomerase from ruining the repair.

Thefindings have immediate implications for researchers and clinicians involved in CRISPR gene editing and that telomerase can add telomeric DNA to the DNA ends made during CRISPR editing. This could potentially lead to insertion of telomeric DNA or formation of a telomere at the site where CRISPR editing was intended.

Reference: DOI: 10.1126/science.adg3224