Nucleic Acids Research Advance Access originally published online on June 18, 2007
Nucleic Acids Research 2007 35(13):4313-4321; doi:10.1093/nar/gkm436
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Nucleic Acids Research, 2007, Vol. 35, No. 13 4313-4321
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Molecular Biology |
Different structural states in oligonucleosomes are required for early versus late steps of base excision repair
1Biochemistry and Biophysics, School of Molecular Biosciences, Washington State University, Pullman, WA 99164-4660 and 2National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, NC 27709-2233, USA
*To whom correspondence should be addressed. Tel: +509-335-6853; Fax: +509-335-9688; Email: smerdon{at}wsu.edu
Received March 9, 2007. Revised May 15, 2007. Accepted May 15, 2007.
Chromatin in eukaryotic cells is folded into higher order structures of folded nucleosome filaments, and DNA damage occurs at all levels of this structural hierarchy. However, little is known about the impact of higher order folding on DNA repair enzymes. We examined the catalytic activities of purified human base excision repair (BER) enzymes on uracil-containing oligonucleosome arrays, which are folded primarily into 30 nm structures when incubated in repair reaction buffers. The catalytic activities of uracil DNA glycosylase (UDG) and apyrimidinic/apurinic endonuclease (APE) digest G:U mismatches to completion in the folded oligonucleosomes without requiring significant disruption. In contrast, DNA polymerase β (Pol β) synthesis is inhibited in a major fraction (
80%) of the oligonucleosome array, suggesting that single strand nicks in linker DNA are far more accessible to Pol β in highly folded oligonucleosomes. Importantly, this barrier in folded oligonucleosomes is removed by purified chromatin remodeling complexes. Both ISW1 and ISW2 from yeast significantly enhance Pol β accessibility to the refractory nicked sites in oligonucleosomes. These results indicate that the initial steps of BER (UDG and APE) act efficiently on highly folded oligonucleosome arrays, and chromatin remodeling may be required for the latter steps of BER in intact chromatin.
Present address: Shima Nakanishi, Stowers Medical Research Institute, 1000 E, 50th Street, Kansas City, MO 64110, USA
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