Double-strand breaks are a cataclysmic threat to genome integrity. In higher eukaryotes the predominant recourse is the nonhomologous end-joining (NHEJ) double-strand break repair pathway. NHEJ is a versatile mechanism employing the Ku heterodimer, ligase IV/XRCC4 and a host of other proteins that juxtapose two free DNA ends for ligation. A critical function of telomeres is their ability to distinguish the ends of linear chromosomes from double-strand breaks, and avoid NHEJ. Telomeres accomplish this feat by forming a unique higher order nucleoprotein structure. Paradoxically, key components of NHEJ associate with normal telomeres and are required for proper length regulation and end protection. Here we review the biochemical mechanism of NHEJ in double-strand break repair, and in the response to dysfunctional telomeres. We discuss the ways in which NHEJ proteins contribute to telomere biology, and highlight how the NHEJ machinery and the telomere complex are evolving to maintain genome stability.
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