ATR blocks telomerase from converting DNA breaks into telomeres

Area of Science:

• Molecular Biology
• Genetics
• Cell Biology

Background:

• Telomeres protect chromosome ends, and telomerase maintains their length.
• Telomerase activity at DNA double-strand breaks (DSBs) can lead to genome instability.
• Neotelomere formation at DSBs can result in terminal truncations.

Purpose of the Study:

• To investigate the role of telomerase at induced DSBs in human cells.
• To identify mechanisms that regulate telomerase activity at DSBs.
• To understand the implications of neotelomere formation for genome integrity.

Main Methods:

• Developed a novel assay to detect neotelomere formation at Cas9- or I-SceI-induced DSBs.
• Utilized human cell lines for experimental analysis.
• Investigated the role of ataxia telangiectasia and Rad3-related (ATR) kinase signaling.

Main Results:

• Telomerase was found to add telomeric repeats to DSBs, causing interstitial telomeric repeat insertions or functional neotelomeres with terminal deletions.
• ATR kinase signaling inhibited telomerase activity at resected DSBs, mitigating the threat to genome integrity.
• Telomerase utilized extruded strands in Cas9 enzyme-product complexes as primers for neotelomere formation.

Conclusions:

• Neotelomere formation by telomerase poses a threat to genome integrity in normal human cells.
• ATR-mediated inhibition of telomerase at DSBs is a crucial protective mechanism.
• Neotelomere formation may provide a survival advantage for cancer cells by preventing breakage-fusion-bridge cycles.