Removal of Shelterin Reveals the Telomere End-Protection Problem

Not Broken Until Repaired Humans, and indeed most eukaryotes, have linear chromosomes with two DNA ends, known as telomeres. Cells have evolved sophisticated systems to repair broken chromosomes, which specifically recognize DNA ends as damage. Telomeres are protected from these repair systems, which would otherwise wreak havoc in the cell, causing genome aberrations that, ironically, can lead to cancer. To understand all the possible threats to telomeres Sfeir and de Lange (p. 593) mutated components of the mouse shelterin protein complex, which forms a protective cap over the telomere ends, rendering telomeres completely devoid of the complex (and packaged only in nucleosomal chromatin). These “naked” telomeres were vulnerable to six DNA repair–related pathways: classical and alternative nonhomologous end joining; ATM and ATR signaling pathways; homology directed recombination; and unmitigated DNA resection. “Naked” chromosome ends are mistakenly targeted by six different DNA repair–related systems in the cell. The telomere end-protection problem is defined by the aggregate of DNA damage signaling and repair pathways that require repression at telomeres. To define the end-protection problem, we removed the whole shelterin complex from mouse telomeres through conditional deletion of TRF1 and TRF2 in nonhomologous end-joining (NHEJ) deficient cells. The data reveal two DNA damage response pathways not previously observed upon deletion of individual shelterin proteins. The shelterin-free telomeres are processed by microhomology-mediated alternative-NHEJ when Ku70/80 is absent and are attacked by nucleolytic degradation in the absence of 53BP1. The data establish that the end-protection problem is specified by six pathways [ATM (ataxia telangiectasia mutated) and ATR (ataxia telangiectasia and Rad3 related) signaling, classical-NHEJ, alt-NHEJ, homologous recombination, and resection] and show how shelterin acts with general DNA damage response factors to solve this problem.

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