Aag-initiated base excision repair drives alkylation-induced retinal degeneration in mice

被引：69

作者：

Meira, Lisiane B. ^{[1
,2
]}

Moroski-Erkul, Catherine A. ^{[1
,2
]}

Green, Stephanie L. ^{[1
,2
]}

Calvo, Jennifer A. ^{[1
,2
]}

Bronson, Roderick T. ^{[3
]}

Shah, Dharini ^{[1
,2
]}

Samson, Leona D. ^{[1
,2
]}

机构：

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

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

[3] Harvard Univ, Sch Med, Rodent Histopathol Lab, Boston, MA 02115 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2009年 / 106卷 / 03期

基金：

美国国家卫生研究院;

关键词：

alkylation damage; DNA glycosylase; photoreceptors; apoptosis; METHYL-N-NITROSOUREA; DNA-POLYMERASE-BETA; PHOTORECEPTOR APOPTOSIS; ENHANCED EXPRESSION; MUTATOR PHENOTYPE; OXIDATIVE STRESS; TUMOR-CELLS; NULL MICE; GLYCOSYLASE; DEFICIENT;

D O I：

10.1073/pnas.0807030106

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Vision loss affects > 3 million Americans and many more people worldwide. Although predisposing genes have been identified their link to known environmental factors is unclear. In wild-type animals DNA alkylating agents induce photoreceptor apoptosis and severe retinal degeneration. Alkylation-induced retinal degeneration is totally suppressed in the absence of the DNA repair protein alkyladenine DNA glycosylase (Aag) in both differentiating and postmitotic retinas. Moreover, transgenic expression of Aag activity restores the alkylation sensitivity of photoreceptors in Aag null animals. Aag heterozygotes display an intermediate level of retinal degeneration, demonstrating haploinsufficiency and underscoring that Aag expression confers a dominant retinal degeneration phenotype.

引用

页码：888 / 893

页数：6

共 43 条

[1]

Bergoglio V, 2002, CANCER RES, V62, P3511

[2] Enhanced expression and activity of DNA polymerase β in human ovarian tumor cells:: impact on sensitivity towards antitumor agents [J].

Bergoglio, V ;

Canitrot, Y ;

Hogarth, L ;

Minto, L ;

Howell, SB ;

Cazaux, C ;

Hoffmann, JS .

ONCOGENE, 2001, 20 (43) :6181-6187

[3]

Brody Jerome S, 2006, Proc Am Thorac Soc, V3, P535, DOI 10.1513/pats.200603-089MS

[4]

Canitrot Y, 2006, ANTICANCER RES, V26, P523

[5] Overexpression of DNA polymerase β in cell results in a mutator phenotype and a decreased sensitivity to anticancer drugs [J].

Canitrot, Y ;

Cazaux, C ;

Fréchet, M ;

Bouayadi, K ;

Lesca, C ;

Salles, B ;

Hoffmann, JS .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (21) :12586-12590

[6] Oxidative stress induces caspase-independent retinal apoptosis in vitro [J].

Carmody, RJ ;

Cotter, TG .

CELL DEATH AND DIFFERENTIATION, 2000, 7 (03) :282-291

[7] Cell fate determination in the vertebrate retina [J].

Cepko, CL ;

Austin, CP ;

Yang, XJ ;

Alexiades, M .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1996, 93 (02) :589-595

[8] 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

[9] DNA repair methyltransferase (Mgmt) knockout mice are sensitive to the lethal effects of chemotherapeutic alkylating agents [J].

Glassner, BJ ;

Weeda, G ;

Allan, JM ;

Broekhof, JLM ;

Carls, NHE ;

Donker, I ;

Engelward, BP ;

Hampson, RJ ;

Hersmus, R ;

Hickman, MJ ;

Broth, RB ;

Warren, HB ;

Wu, MM ;

Hoeijmakers, JHJ ;

Samson, LD .

MUTAGENESIS, 1999, 14 (03) :339-347

[10] Generation of a strong mutator phenotype in yeast by imbalanced base excision repair [J].

Glassner, BJ ;

Rasmussen, LJ ;

Najarian, MT ;

Posnick, LM ;

Samson, LD .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (17) :9997-10002

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