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TRF2 interaction with Ku heterotetramerization interface gives insight into c-NHEJ prevention at human telomeres.

ABSTRACT: Telomeres are protected from nonhomologous end-joining (NHEJ) to avoid deleterious chromosome fusions, yet they associate with the Ku heterodimer that is principal in the classical NHEJ (c-NHEJ) pathway. T-loops have been proposed to inhibit Ku's association with telomeric ends, thus inhibiting c-NHEJ; however, deficiencies in the t-loop model suggest additional mechanisms are in effect. We demonstrate that TRF2 interacts with Ku at telomeres and via residues in Ku70 helix 5 (?5), which are vital for NHEJ. We show that Ku's interaction with a TRF2 mutant that induces telomeric fusions is significantly impaired. Additionally, we demonstrate that Ku70 ?5 is required for Ku self-association in live cells, which can bridge DNA ends. Together, these findings lead us to propose a model in which telomeres are directly protected from c-NHEJ via TRF2 impeding Ku's ability to synapse telomere ends.

SUBMITTER: Ribes-Zamora A

PROVIDER: S-EPMC3984498 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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TRF2 interaction with Ku heterotetramerization interface gives insight into c-NHEJ prevention at human telomeres.

Ribes-Zamora Albert A Indiviglio Sandra M SM Mihalek Ivana I Williams Christopher L CL Bertuch Alison A AA

Cell reports 20131003 1

Telomeres are protected from nonhomologous end-joining (NHEJ) to avoid deleterious chromosome fusions, yet they associate with the Ku heterodimer that is principal in the classical NHEJ (c-NHEJ) pathway. T-loops have been proposed to inhibit Ku's association with telomeric ends, thus inhibiting c-NHEJ; however, deficiencies in the t-loop model suggest additional mechanisms are in effect. We demonstrate that TRF2 interacts with Ku at telomeres and via residues in Ku70 helix 5 (α5), which are vita ...[more]

PMID: 24095731

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