Molecular Biology

Facing in Two Directions

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Science  16 Mar 2007:
Vol. 315, Issue 5818, pp. 1467
DOI: 10.1126/science.315.5818.1467a

The ends of DNA molecules can be extremely dangerous to a cell because of their potential to recombine with other DNA sequences, which would cause large-scale disruption of genome integrity. Double-stranded DNA ends are found naturally at the termini (called telomeres) of linear eukaryotic chromosomes and also at sites of spontaneous genomic damage. Exposed ends at both locations are recognized by the evolutionarily conserved Ku heterodimer, which is required for the nonhomologous end-joining (NHEJ) repair of broken DNA as well as for the silencing of genes at telomeres. How does Ku orchestrate such distinct functions? The Ku heterodimer consists of the structurally and evolutionarily related Ku70 and Ku80 proteins, which together form a ring that wraps around DNA ends. The N-terminal domains of the two subunits face in opposite directions when bound to DNA, with Ku70 oriented toward the DNA ends. Ribes-Zamora et al. have carried out a mutagenesis study of yeast Ku and show that an αhelix in the Ku70 N-terminal domain is required for DNA repair, possibly as a surface to which NHEJ factors are recruited. The equivalent helix in Ku80 is required for telomeric silencing, which is consistent with its facing toward the bulk of the telomeric structure when Ku is bound at telomeres. Prokaryotes contain a single Ku gene that is involved in DNA repair, and most lack telomeres, having circular genomes. The advent of linear chromosomes and telomeres in eukaryotes probably favored the duplication of the Ku gene and the subsequent functional differentiation of the Ku70 and Ku80 subunits. — GR

Nat. Struct. Mol. Biol. 10.1038/nsmb1214 (2007).

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