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PMID:24095731

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Citation

Ribes-Zamora, A, Indiviglio, SM, Mihalek, I, Williams, CL and Bertuch, AA (2013) TRF2 interaction with Ku heterotetramerization interface gives insight into c-NHEJ prevention at human telomeres. Cell Rep 5:194-206

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 (α5), 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 α5 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.

Links

PubMed PMC3984498 Online version:10.1016/j.celrep.2013.08.040

Keywords

Antigens, Nuclear/chemistry; Antigens, Nuclear/genetics; Antigens, Nuclear/metabolism; DNA End-Joining Repair; DNA-Binding Proteins/chemistry; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Humans; Ku Autoantigen; Models, Molecular; Protein Multimerization; Recombination, Genetic; Telomere/chemistry; Telomere/genetics; Telomere/metabolism; Telomeric Repeat Binding Protein 2/genetics; Telomeric Repeat Binding Protein 2/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:XRCC6

part_of

GO:0043564: Ku70:Ku80 complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:XRCC6

involved_in

GO:0097680: double-strand break repair via classical nonhomologous end joining

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:XRCC6

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13426

F

Seeded From UniProt

complete

HUMAN:XRCC6

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9H9Q4

F

Seeded From UniProt

complete

HUMAN:XRCC6

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P54274

F

Seeded From UniProt

complete

HUMAN:XRCC6

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q15554

F

Seeded From UniProt

complete

HUMAN:XRCC6

involved_in

GO:0000723: telomere maintenance

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:XRCC5

part_of

GO:0043564: Ku70:Ku80 complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:XRCC5

involved_in

GO:0032204: regulation of telomere maintenance

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TERF1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P12956

F

Seeded From UniProt

complete

HUMAN:XRCC4

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P12956

F

Seeded From UniProt

complete

HUMAN:TERF2

enables

GO:0044877: protein-containing complex binding

ECO:0000353: physical interaction evidence used in manual assertion

ComplexPortal:CPX-1993

F

Seeded From UniProt

complete

HUMAN:TERF2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P12956

F

Seeded From UniProt

complete

HUMAN:TERF2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9NYB0

F

Seeded From UniProt

complete

HUMAN:TERF2

involved_in

GO:0016233: telomere capping

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NHEJ1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P12956

F

Seeded From UniProt

complete

HUMAN:TE2IP

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q15554

F

Seeded From UniProt

complete

HUMAN:TERF2

enables

GO:0044877: protein-containing complex binding

ECO:0000353: physical interaction evidence used in manual assertion

ComplexPortal:CPX-1993

F

occurs_at:(GO:0000781)

Seeded From UniProt

complete

HUMAN:TERF2

involved_in

GO:0031848: protection from non-homologous end joining at telomere

ECO:0000353: physical interaction evidence used in manual assertion

ComplexPortal:CPX-1993

P

Seeded From UniProt

complete

Notes

See also

References

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