AlkB reverses etheno DNA lesions caused by lipid oxidation in vitro and in vivo

被引：161

作者：

Delaney, JC

Smeester, L

Wong, CY

Frick, LE

Taghizadeh, K

Wishnok, JS

Drennan, CL

Samson, LD

Essigmann, JM

机构：

[1] MIT, Biol Engn Div, Cambridge, MA 02139 USA

[2] MIT, Environm Hlth Sci Ctr, Cambridge, MA 02139 USA

[3] MIT, Dept Chem, Cambridge, MA 02139 USA

[4] MIT, Dept Biol, Cambridge, MA 02139 USA

来源：

NATURE STRUCTURAL & MOLECULAR BIOLOGY | 2005年 / 12卷 / 10期

关键词：

D O I：

10.1038/nsmb996

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Oxidative stress converts lipids into DNA-damaging agents. The genomic lesions formed include 1, N-6-ethenoadenine (epsilon A) and 3,N-4-ethenocytosine (epsilon C), in which two carbons of the lipid alkyl chain form an exocyclic adduct with a DNA base. Here we show that the newly characterized enzyme AlkB repairs epsilon A and epsilon C. The potent toxicity and mutagenicity of epsilon A in Escherichia coli lacking AlkB was reversed in AlkB(+) cells; AlkB also mitigated the effects of epsilon C. In vitro, AlkB cleaved the lipid-derived alkyl chain from DNA, causing epsilon A and epsilon C to revert to adenine and cytosine, respectively. Biochemically, epsilon A is epoxidized at the etheno bond. The epoxide is putatively hydrolyzed to a glycol, and the glycol moiety is released as glyoxal. These reactions show a previously unrecognized chemical versatility of AlkB. In mammals, the corresponding AlkB homologs may defend against aging, cancer and oxidative stress.

引用

收藏

页码：855 / 860

页数：6

相关论文

共 40 条

[11] Lipid peroxidation as a potential endogenous source for the formation of exocyclic DNA adducts [J].

Chung, FL ;

Chen, HJC ;

Nath, RG .

CARCINOGENESIS, 1996, 17 (10) :2105-2111

[12] Reactive nitrogen species in the chemical biology of inflammation [J].

Dedon, PC ;

Tannenbaum, SR .

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 2004, 423 (01) :12-22

[13] Mutagenesis, genotoxicity, and repair of 1-methyladenine, 3-alkylcytosines, 1-methylguanine and 3-methylthymine, in alkB Escherichia coli [J].

Delaney, JC ;

Essigmann, JM .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (39) :14051-14056

[14] Reversal of DNA alkylation damage by two human dioxygenases [J].

Duncan, T ;

Trewick, SC ;

Koivisto, P ;

Bates, PA ;

Lindahl, T ;

Sedgwick, B .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (26) :16660-16665

[15] FORMATION OF 1,N-6-ETHENOADENILLE AND 3,N-4-ETHENOCYTOSINE BY LIPID-PEROXIDATION PRODUCTS AND NUCLEIC-ACID BASES [J].

ELGHISSASSI, F ;

BARBIN, A ;

NAIR, J ;

BARTSCH, H .

CHEMICAL RESEARCH IN TOXICOLOGY, 1995, 8 (02) :278-283

[16] Base excision repair deficient mice lacking the Aag alkyladenine DNA glycosylase [J].

Engelward, BP ;

Weeda, G ;

Wyatt, MD ;

Broekhof, JLM ;

deWit, J ;

Donker, I ;

Allan, JM ;

Gold, B ;

Hoeijmakers, JHJ ;

Samson, LD .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (24) :13087-13092

[17] Oxidative DNA damage and disease: induction, repair and significance [J].

Evans, MD ;

Dizdaroglu, M ;

Cooke, MS .

MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH, 2004, 567 (01) :1-61

[18] AlkB-mediated oxidative demethylation reverses DNA damage in Escherichia coli [J].

Falnes, PO ;

Johansen, RF ;

Seeberg, E .

NATURE, 2002, 419 (6903) :178-182

[19] Repair of 3-methylthymine and 1-methylguanine lesions by bacterial and human AlkB proteins [J].

Falnes, PO .

NUCLEIC ACIDS RESEARCH, 2004, 32 (21) :6260-6267

[20] New immunoaffinity-LC-MS/MS methodology reveals that Aag null mice are deficient in their ability to clear 1,N6-etheno-deoxyadenosine DNA lesions from lung and liver in vivo [J].

Ham, AJL ;

Engelward, BP ;

Koc, H ;

Sangaiah, R ;

Meira, LB ;

Samson, LD ;

Swenberg, JA .

DNA REPAIR, 2004, 3 (03) :257-265

← 1 2 3 4 →