Removal of Shelterin Reveals the Telomere End-Protection Problem

Abstract

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.