Molekuláris Sejt- és Immunbiológia Doktori Iskola

Állandó link (URI) ehhez a gyűjteményhez

https://hdl.handle.net/2437/31600

Általános Orvostudományi Kar

Molekuláris Sejt- és Immunbiológia Doktori Iskola
(vezető: Dr. Balogh István)

Orvostudományi doktori tanács

D183

tudományág:
- elméleti orvostudományok

Böngészés

Molekuláris Sejt- és Immunbiológia Doktori Iskola Tárgyszó szerinti böngészés "8-Oxoguanine DNA glycosylase-1 (Ogg1)"

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    8-Oxoguanine DNA glycosylase-1 links DNA repair to cellular responses via the activation of the small GTPases, Ras and Rac1
    Hajas, György; Bácsi, Attila; Molekuláris sejt- és immunbiológia doktori iskola
    DNA is a frequent target of oxidative agents from both inner and outer sources. One of the most studied DNA adduct among the oxidized bases is 8-oxoG and determination of its level can be used as a reliable gauge of the oxidative stress load of an organism. The 8-oxoguanine DNA glycosylase 1 is the dedicated enzyme to excise the 8-oxoG during the DNA base excision repair process from nuclear and mitochondrial genomes. Accumulation of 8-oxoG in the DNA connected to various disorders like cancer, aging, Alzheimer disease, although OGG1 knock-out mice have normal life span, show only moderate increases in tumor formation, have an increased tolerance to chronic oxidative stress and are less susceptible to inflammatory processes. In this work we describe that OGG1 can exert non-repair functions after binding its excised product, 8-oxoG. We demonstrated that OGG1 has a non-catalytic binding site for 8-oxoG. In a complex with its product, OGG1 not only becomes more efficient removing oxidized guanine, but also goes through sterical changes, which enable its physical interaction with small GTPases, Ras and Rac1 proteins. These interactions result in GDP to GTP exchange activating these small GTPases. We found that intranasal administration of 8-oxoG increases both Ras-GTP and Rac1-GTP levels in the lungs of experimental mice. Our results also show that both externally added and intracellularly generated 8-oxoG bases are able to form a complex with OGG1 leading to Ras activation. We revealed that OGG1/8-oxoG complex formation can lead to MEK/ERK phosphorylation via Ras or a NOX4-mediated increase in cellular ROS levels via Rac1. While the biological significance of our findings has yet to be fully elucidated, it appears that activation of the small GTPase Rac1, leading to localized ROS generation could be part of a physiological DNA damage/repair response initiated by OGG1. As the OGG1/8-oxoG not only activates Rac1 but also the canonical Ras family GTPases, it could be considered that Rac1/NOX4/ROS and Ras-mediated signaling are involved in maintaining cellular homeostasis. We also speculate that a failure in the control of OGG1 activity may lead to excessive release of 8-oxoG from DNA, resulting in unscheduled activation of Rac and Ras family GTPases that could result in pathophysiological cellular responses, contributing to diseases, cellular senescence, and aging processes.