Protein binding has a large effect on radical mediated DNA damage.
Oxidative DNA damage is important in aging and a variety of diseases. Significant advances have been made in our understanding of the chemistry of radical mediated DNA damage. These studies have been carried out on DNA in the absence of proteins. However, in cells DNA is typically bound by proteins such as in chromatin and transiently by proteins that regulate biochemical processes. How and whether protein binding affects DNA radical reactivity is not well understood. The effect of the DNA binding protein Hbb on the reactivity of the 5-(2'-deoxyuridinyl)methyl radical (1) and 5-(2'-deoxycytidinyl)methyl radical (2) was studied. Hbb bends DNA and disrupts base stacking at the sites of kinking. The reactivity of 1 and 2 are significantly affected when they are generated at the kinking site in the presence of Hbb. The increased conformational mobility of the radicals results in significantly higher yields of DNA interstrand cross-links. These studies provide the first specific data on how protein binding affects the reactivity of a DNA radical and bring us closer to understanding oxidative DNA damage in cells.
Peng
Xiaohua
X
Department of Chemistry, The Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland 21218, USA.
Pigli
Ying Z
YZ
Rice
Phoebe A
PA
Greenberg
Marc M
MM
D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism*; D001483:Base Sequence; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry* / Q000378:metabolism*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D003857:Deoxyuridine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D005609:Free Radicals / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D011485:Protein Binding; D017433:Protein Structure, Secondary; D013438:Sulfhydryl Compounds / Q000737:chemistry
C510308:5-(2'-deoxyuridinyl)methyl; D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D005609:Free Radicals; C102676:Hbb protein, Borrelia burgdorferi; D013438:Sulfhydryl Compounds; D004247:DNA; D003857:Deoxyuridine
J Am Chem Soc. 2006 Jan 18;128(2):485-91
16402835
Mol Microbiol. 2000 Jul;37(1):145-55
10931312
Biochemistry. 2001 May 8;40(18):5556-64
11331021
Chem Rev. 2006 Feb;106(2):277-301
16464006
Annu Rev Biochem. 2002;71:51-70
12045090
Mutat Res. 2003 Oct 29;531(1-2):5-23
14637244
J Am Chem Soc. 2005 Mar 23;127(11):3692-3
15771492
Org Biomol Chem. 2007 Jan 7;5(1):18-30
17164902
Mutat Res. 2004 Sep;567(1):1-61
15341901
Nature. 2000 Nov 9;408(6809):248-54
11089982
Nature. 1997 Sep 18;389(6648):251-60
9305837
Chem Res Toxicol. 1998 Nov;11(11):1235-48
9815182
Mol Microbiol. 2007 Mar;63(5):1319-30
17244195
Chembiochem. 2005 Jan;6(1):27-32
15637664
Free Radic Biol Med. 2008 Apr 15;44(8):1493-505
18258207
Radiat Prot Dosimetry. 2006;122(1-4):106-9
17229785
J Am Chem Soc. 2008 Aug 6;130(31):10299-306
18620398
Cell. 2005 Feb 25;120(4):497-512
15734682
Curr Opin Struct Biol. 2004 Feb;14(1):28-35
15102446