Published online 24 February 2005
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Oxidative damage in telomeric DNA disrupts recognition by TRF1 and TRF2
Laboratory of Molecular Gerontology, National Institute on Aging NIH, Baltimore, MD 21224, USA 1 Department of Molecular/Cell Biology, Georgia Institute of Technology Atlanta, GA 30332, USA
*To whom correspondence should be addressed. Tel: +1 410 558 8162; Fax: +1 410 558 8157; Email: opreskopa{at}grc.nia.nih.gov
Received January 14, 2005. Revised February 9, 2005. Accepted February 9, 2005.
The ends of linear chromosomes are capped by protein–DNA complexes termed telomeres. Telomere repeat binding factors 1 and 2 (TRF1 and TRF2) bind specifically to duplex telomeric DNA and are critical components of functional telomeres. Consequences of telomere dysfunction include genomic instability, cellular apoptosis or senescence and organismal aging. Mild oxidative stress induces increased erosion and loss of telomeric DNA in human fibroblasts. We performed binding assays to determine whether oxidative DNA damage in telomeric DNA alters the binding activity of TRF1 and TRF2 proteins. Here, we report that a single 8-oxo-guanine lesion in a defined telomeric substrate reduced the percentage of bound TRF1 and TRF2 proteins by at least 50%, compared with undamaged telomeric DNA. More dramatic effects on TRF1 and TRF2 binding were observed with multiple 8-oxo-guanine lesions in the tandem telomeric repeats. Binding was likewise disrupted when certain intermediates of base excision repair were present within the telomeric tract, namely abasic sites or single nucleotide gaps. These studies indicate that oxidative DNA damage may exert deleterious effects on telomeres by disrupting the association of telomere-maintenance proteins TRF1 and TRF2.
Correspondence may also be addressed to Vilhelm A. Bohr. Email: vbohr{at}nih.gov
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