Detection of damaged DNA bases by DNA glycosylase enzymes.
A fundamental and shared process in all forms of life is the use of DNA glycosylase enzymes to excise rare damaged bases from genomic DNA. Without such enzymes, the highly ordered primary sequences of genes would rapidly deteriorate. Recent structural and biophysical studies are beginning to reveal a fascinating multistep mechanism for damaged base detection that begins with short-range sliding of the glycosylase along the DNA chain in a distinct conformation we call the search complex (SC). Sliding is frequently punctuated by the formation of a transient "interrogation" complex (IC) where the enzyme extrahelically inspects both normal and damaged bases in an exosite pocket that is distant from the active site. When normal bases are presented in the exosite, the IC rapidly collapses back to the SC, while a damaged base will efficiently partition forward into the active site to form the catalytically competent excision complex (EC). Here we review the unique problems associated with enzymatic detection of rare damaged DNA bases in the genome and emphasize how each complex must have specific dynamic properties that are tuned to optimize the rate and efficiency of damage site location.
Friedman
Joshua I
JI
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, WBSB 314, 725 North Wolfe Street, Baltimore, Maryland 21205, USA.
Stivers
James T
JT
D004247:DNA / Q000737:chemistry*; D004249:DNA Damage; D045647:DNA Glycosylases / Q000737:chemistry*; D004260:DNA Repair; D043382:DNA-Formamidopyrimidine Glycosylase / Q000737:chemistry; D029968:Escherichia coli Proteins / Q000737:chemistry; D006147:Guanine / Q000031:analogs & derivatives / Q000737:chemistry; D007700:Kinetics; D013379:Substrate Specificity; D014498:Uracil / Q000737:chemistry; D051981:Uracil-DNA Glycosidase / Q000737:chemistry
D029968:Escherichia coli Proteins; C024829:8-hydroxyguanine; D014498:Uracil; D006147:Guanine; D004247:DNA; D045647:DNA Glycosylases; D051981:Uracil-DNA Glycosidase; C479058:oxoguanine glycosylase 1, human; D043382:DNA-Formamidopyrimidine Glycosylase; C468610:DNA-formamidopyrimidine glycosylase, E coli
J Biol Chem. 2002 May 31;277(22):19424-32
11907039
EMBO J. 2007 May 2;26(9):2411-20
17410210
Chem Rev. 2006 Feb;106(2):489-505
16464016
Biochem Soc Trans. 2009 Apr;37(Pt 2):343-8
19290859
Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):15883-8
16243975
Mol Cell. 2010 Mar 12;37(5):702-13
20227373
Mol Cell. 2003 Jun;11(6):1647-59
12820976
Mutat Res. 2005 Sep 4;577(1-2):24-54
15939442
Biochemistry. 2003 Jan 28;42(3):801-10
12534293
Chem Biol. 2002 Mar;9(3):345-50
11927259
Chem Rev. 2003 Jul;103(7):2729-59
12848584
Nature. 2007 Sep 27;449(7161):433-7
17704764
Proc Natl Acad Sci U S A. 2000 May 9;97(10):5083-8
10805771
J Am Chem Soc. 2005 Oct 12;127(40):13906-18
16201812
Nature. 1996 Nov 7;384(6604):87-92
8900285
Nature. 2000 Feb 24;403(6772):859-66
10706276
Mutat Res. 1993 Aug;294(2):109-16
7687003
Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):8890-5
18587051
Nat Struct Mol Biol. 2009 Dec;16(12):1224-9
19898474
J Am Chem Soc. 2008 Apr 30;130(17):5789-97
18393424
Nucleic Acids Res. 2005 Jul 15;33(12):3919-31
16024742
Mol Microbiol. 2005 Aug;57(4):889-99
16091032
Proc Natl Acad Sci U S A. 1974 Sep;71(9):3649-53
4610583
FEBS Lett. 2008 Feb 6;582(3):410-4
18201572
Mutat Res. 2010 Mar 1;685(1-2):3-10
19751748
J Biol Chem. 2003 Jan 24;278(4):2411-8
12441341
J Biol Chem. 2010 Jan 22;285(4):2876-85
19933279
Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10791-6
18669665
Trends Cell Biol. 2002 Nov;12(11):491-5
12446102
J Biol Chem. 2003 Dec 19;278(51):51543-8
14525999
Biochemistry. 1992 Sep 15;31(36):8421-8
1327102
Nature. 2004 Feb 12;427(6975):652-6
14961129
Proc Natl Acad Sci U S A. 2000 Dec 5;97(25):13573-8
11106395
Biochemistry. 2008 Nov 4;47(44):11434-45
18839966
Nucleic Acids Res. 2009 Jun;37(11):3493-500
19339520
J Biol Chem. 1998 Dec 18;273(51):34057-62
9852062
Nucleic Acids Res. 2003 Mar 1;31(5):1434-43
12595551
J Mol Biol. 2009 Jan 30;385(4):1087-97
19059266
EMBO J. 2000 Feb 15;19(4):758-66
10675345
Mutat Res. 2010 Mar 1;685(1-2):11-20
19909758
Biochemistry. 1995 May 9;34(18):6109-19
7742315
Chemistry. 2008;14(3):786-93
18000994
Nucleic Acids Res. 1980 Nov 11;8(21):5113-27
6255442
Nucleic Acids Res. 2001 Aug 1;29(15):3219-30
11470880
Carcinogenesis. 2001 Mar;22(3):387-93
11238177
Proc Natl Acad Sci U S A. 2006 Apr 11;103(15):5752-7
16585517
Biochemistry. 2005 Apr 26;44(16):5949-59
15835884
Nature. 2007 Jun 21;447(7147):941-50
17581577
EMBO J. 2003 Jul 1;22(13):3461-71
12840008
J Biol Chem. 2007 Jan 12;282(2):1029-38
17090545
J Biol Chem. 1994 Sep 2;269(35):22046-53
8071327
Biochemistry. 2003 Nov 4;42(43):12455-60
14580190
J Am Chem Soc. 2006 Oct 11;128(40):13034-5
17017766
Biochemistry. 2002 Sep 17;41(37):11248-54
12220190
Annu Rev Biochem. 1998;67:181-98
9759487
Science. 2006 Feb 24;311(5764):1153-7
16497933
Cell. 1995 Dec 1;83(5):773-82
8521494
Nucleic Acids Res. 2007;35(5):1478-87
17284454
Nature. 2005 Mar 31;434(7033):612-8
15800616
Biochemistry. 2000 Nov 21;39(46):14054-64
11087352
Nucleic Acids Res. 2004 Jun 03;32(10):3040-52
15178741
Biochemistry. 2008 Aug 26;47(34):8970-6
18672903
Biochemistry. 2002 Sep 17;41(37):11236-47
12220189
Proc Natl Acad Sci U S A. 2006 Oct 10;103(41):15020-5
17015827
Nature. 2009 Dec 10;462(7274):762-6
20010681
Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7465-70
12799467
Cell. 1998 Oct 16;95(2):249-58
9790531
Annu Rev Biochem. 2006;75:519-41
16756501
Nucleic Acids Res. 2004 Feb 09;32(3):926-35
14769949
Nat Struct Mol Biol. 2004 Dec;11(12):1230-6
15558051
Nature. 1993 Apr 22;362(6422):709-15
8469282
Biochemistry. 2000 Oct 17;39(41):12585-94
11027138