Telomere-binding protein TRF2 binds to and stimulates the Werner and Bloom syndrome helicases.
Werner syndrome is a human premature aging disorder displaying cellular defects associated with telomere maintenance including genomic instability, premature senescence, and accelerated telomere erosion. The yeast homologue of the Werner protein (WRN), Sgs1, is required for recombination-mediated lengthening of telomeres in telomerase-deficient cells. In human cells, we report that WRN co-localizes and physically interacts with the critical telomere maintenance protein TRF2. This interaction is mediated by the RecQ conserved C-terminal region of WRN. In vitro, TRF2 demonstrates high affinity for WRN and for another RecQ family member, the Bloom syndrome protein (BLM). TRF2 interaction with either WRN or BLM results in a notable stimulation of their helicase activities. Furthermore, the WRN and BLM helicases, partnered with replication protein A, actively unwind long telomeric duplex regions that are pre-bound by TRF2. These results suggest that TRF2 functions with WRN, and possibly BLM, in a common pathway at telomeric ends.
Opresko
Patricia L
PL
Laboratory of Molecular Gerontology, NIA, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
von Kobbe
Cayetano
C
Laine
Jean-Philippe
JP
Harrigan
Jeanine
J
Hickson
Ian D
ID
Bohr
Vilhelm A
VA
D000251:Adenosine Triphosphatases / Q000378:metabolism*; D001483:Base Sequence; D004265:DNA Helicases / Q000378:metabolism*; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation; D005090:Exodeoxyribonucleases; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006801:Humans; D011485:Protein Binding; D053484:RecQ Helicases; D011994:Recombinant Proteins / Q000378:metabolism; D016615:Telomere; D035341:Telomeric Repeat Binding Protein 2 / Q000378:metabolism*; D000071657:Werner Syndrome Helicase
D017931:DNA Primers; D011994:Recombinant Proteins; D035341:Telomeric Repeat Binding Protein 2; D005090:Exodeoxyribonucleases; D000251:Adenosine Triphosphatases; C097151:Bloom syndrome protein; D004265:DNA Helicases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase