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Shunji Nakatake, Yusuke Murakami, Yasuhiro Ikeda, Noriko Yoshida, Takashi Tachibana, Toshio Hisatomi, Yusaku Nakabeppu, Tatsuro Ishibashi; MUTYH, a Base Excision Repair Enzyme against Oxidative DNA Damage, Induces Single-strand Break Formation and Mediates Photoreceptor Cell Death in a Mouse Model of Retinitis Pigmentosa. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5457.
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© ARVO (1962-2015); The Authors (2016-present)
Oxidative stress has been implicated in the pathogenesis of retinitis pigmentosa (RP). We previously showed that oxidative DNA damage is critical for photoreceptor cell death in animal models of RP. However, its underlying molecular mechanisms have not been fully elucidated. MUTYH, a repair enzyme against oxidative DNA damage, removes the adenine incorrectly inserted opposite 8-oxoguanine (8-oxoG) in template DNA, however under excessive accumulation of 8-oxoG in DNA, removal of adenine by MUTYH leads to the formation of single-strand breaks (SSBs) and cell death. In this study, we investigated the role of MUTYH for oxidative DNA damage repair and photoreceptor cell death in a mouse model of RP.
The eyes of rd10 mice, which have a missense mutation in the Pde6b gene, and Mutyh-deficient rd10 mice (rd10; Mutyh-/- mice) were used for the experiments. Photoreceptor cell death was evaluated by TUNEL staining and measurement of the outer nuclear layer (ONL) thickness. Accumulation of 8-oxoG, a major oxidized base in DNA, was analyzed by immunohistochemistry. Cell death signaling pathways were assessed by immunofluorescence.
Mutyh deficiency substantially reduced the number of TUNEL-positive cells in ONL at postnatal day 21 (P21) (P < 0.01) and attenuated the photoreceptor cell loss at P26 (P < 0.01) in rd10 mice. Accumulation of 8-oxoG in photoreceptor cells was decreased in rd10; Mutyh-/- mice compared with that in rd10 mice. Moreover, Mutyh deficiency suppressed SSB formation, poly (ADP-ribose) polymerase activation, and nuclear translocation of apoptosis-inducing factor.
MUTYH-mediated base excision repair is crucial in SSB formation and photoreceptor cell death during oxidative DNA damage in a mouse model of RP, suggesting MUTYH as a potential target to prevent or delay photoreceptor cell loss in RP.
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