Aag-initiated base excision repair drives alkylation-induced retinal degeneration in mice.
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.
Meira
Lisiane B
LB
Department of Biological Engineering and Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Moroski-Erkul
Catherine A
CA
Green
Stephanie L
SL
Calvo
Jennifer A
JA
Bronson
Roderick T
RT
Shah
Dharini
D
Samson
Leona D
LD
D000477:Alkylating Agents / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis; D045647:DNA Glycosylases / Q000502:physiology*; D015254:DNA Modification Methylases / Q000502:physiology; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000502:physiology; D008741:Methyl Methanesulfonate / Q000633:toxicity; D008770:Methylnitrosourea / Q000633:toxicity; D051379:Mice; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects; D012162:Retinal Degeneration / Q000139:chemically induced*; D025521:Tumor Suppressor Proteins / Q000502:physiology
D000477:Alkylating Agents; D025521:Tumor Suppressor Proteins; D008770:Methylnitrosourea; D008741:Methyl Methanesulfonate; D015254:DNA Modification Methylases; C528331:MGMT protein, mouse; C021565:3-methyladenine-DNA glycosylase; D045647:DNA Glycosylases; D045643:DNA Repair Enzymes