ATR blocks telomerase from converting DNA breaks into telomeres

Telomerase, the enzyme that maintains telomeres at natural chromosome ends, should be repressed at double-strand breaks (DSBs), where neotelomere formation can cause terminal truncations. We developed an assay to detect neotelomere formation at Cas9- or I-SceI-induced DSBs in human cells. Telomerase...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2024-02, Vol.383 (6684), p.763-770
Main Authors: Kinzig, Charles G, Zakusilo, George, Takai, Kaori K, Myler, Logan R, de Lange, Titia
Format: Article
Language:English
Subjects:
Chromosomes
Damage
Deoxyribonucleic acid
DNA
DNA damage
Genomes
Kinases
Telomerase
Telomeres
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Summary:Telomerase, the enzyme that maintains telomeres at natural chromosome ends, should be repressed at double-strand breaks (DSBs), where neotelomere formation can cause terminal truncations. We developed an assay to detect neotelomere formation at Cas9- or I-SceI-induced DSBs in human cells. Telomerase added telomeric repeats to DSBs, leading to interstitial telomeric repeat insertions or the formation of functional neotelomeres accompanied by terminal deletions. The threat that telomerase poses to genome integrity was minimized by ataxia telangiectasia and Rad3-related (ATR) kinase signaling, which inhibited telomerase at resected DSBs. In addition to acting at resected DSBs, telomerase used the extruded strand in the Cas9 enzyme-product complex as a primer for neotelomere formation. We propose that although neotelomere formation is detrimental in normal human cells, it may allow cancer cells to escape from breakage-fusion-bridge cycles.
ISSN:0036-8075
1095-9203
1095-9203
DOI:10.1126/science.adg3224