Telomerase is reactivated in ~90% of malignant tumours. The biochemical mechanism by which telomere shortening without telomerase causes senescence/apoptosis, and the protein that detects critically short telomeres as 'DNA damage', is:

• A Short telomeres activate mTOR causing metabolic shutdown and senescence
• B Telomere shortening reduces transcription of adjacent genes causing global transcriptional silencing
• C Critically short telomeres activate PARP-1 consuming NAD+ and causing metabolic collapse
• D p53 is activated by ATM/ATR kinases sensing uncapped (unprotected) telomere ends as double-strand breaks ✓

Explanation

Telomeres form a T-loop structure with shelterin proteins (TRF1, TRF2, POT1, etc.) that protect chromosome ends from being recognised as double-strand breaks. When telomeres shorten critically, shelterin is unable to maintain the T-loop, exposing single-stranded G-overhangs and double-strand break-like ends. ATM and ATR kinases recognise these as DNA damage, phosphorylate H2AX (gamma-H2AX) and Chk1/Chk2, activating the p53-p21 pathway causing senescence or apoptosis. Cancer cells upregulate TERT (catalytic subunit of telomerase) — the hTERT promoter mutation is the most common non-coding mutation in many cancers — to maintain telomere length and bypass this checkpoint.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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Written and medically reviewed by the StethoPrep medical team.