It has been proposed that oxidative stress, elicited by high levels of reactive oxygen species, accelerates telomere shortening by erosion of telomeric DNA repeats. While most eukaryotes counteract telomere shortening by telomerase-driven addition of these repeats, telomeric loss in Drosophila is compensated by retrotransposition of the telomeric retroelements HeT-A, TART and TAHRE to chromosome ends. In this study we tested the effect of chronic exposure of flies to non-/sub-lethal doses of paraquat, which is a redox cycling compound widely used to induce oxidative stress in various experimental paradigms including telomere length analyses. Indeed, chronic paraquat exposure for five generations resulted in elevated transcriptional activity of both telomeric and non-telomeric transposable elements, and extended telomeric length in the tested fly lines. We propose that low oxidative stress leads to increased telomere length within Drosophila populations. For a mechanistic understanding of the observed phenomenon we discuss two scenarios: adaption, acting through a direct stimulation of telomere extension, or positive selection favoring individuals with longer telomeres within the population.

• MeSH
• Drosophila melanogaster účinky léků   genetika   MeSH
• genetická transkripce účinky léků   MeSH
• homeostáza telomer účinky léků   MeSH
• hormeze * MeSH
• paraquat farmakologie   MeSH
• reaktivní formy kyslíku farmakologie   MeSH
• retroelementy účinky léků   MeSH
• telomery účinky léků   fyziologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zkracování telomer účinky léků   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

The role of the nucleolus and autophagy in maintenance of nuclear integrity is poorly understood. In addition, the mechanisms of nuclear destruction in cancer cells senesced after conventional chemotherapy are unclear. In an attempt to elucidate these issues, we studied teratocarcinoma PA1 cells treated with Etoposide (ETO), focusing on the nucleolus. Following treatment, most cells enter G2 arrest, display persistent DNA damage and activate p53, senescence, and macroautophagy markers. 2-5 µm sized nucleolar aggresomes (NoA) containing fibrillarin (FIB) and damaged rDNA, colocalized with ubiquitin, pAMPK, and LC3-II emerge, accompanied by heterochromatin fragments, when translocated perinuclearly. Microscopic counts following application of specific inhibitors revealed that formation of FIB-NoA is dependent on deficiency of the ubiquitin proteasome system coupled to functional autophagy. In contrast, the accompanying NoAs release of pericentric heterochromatin, which exceeds their frequency, is favored by debilitation of autophagic flux. Potential survivors release NoA in the cytoplasm during rare mitoses, while exit of pericentric fragments often depleted of H3K9Me3, with or without encompassing by NoA, occurs through the nucleolar protrusions and defects of the nuclear envelope. Foci of LC3-II are accumulated in the nucleoli undergoing cessation of rDNA transcription. As an origin of heterochromatin fragmentation, the unscheduled DNA synthesis and circular DNAs were found in the perinucleolar heterochromatin shell, along with activation and retrotransposition of ALU elements, colocalized with 45S rDNA in NoAs. The data indicate coordination of the basic nucleolar function with autophagy regulation in maintenance of the integrity of the nucleolus associated domains secured by inactivity of retrotransposons.

• MeSH
• autofagie účinky léků   genetika   MeSH
• buněčné jadérko účinky léků   genetika   metabolismus   MeSH
• chromozomální proteiny, nehistonové metabolismus   MeSH
• etoposid toxicita   MeSH
• heterochromatin účinky léků   metabolismus   MeSH
• inhibitor p16 cyklin-dependentní kinasy metabolismus   MeSH
• kontrolní body buněčného cyklu účinky léků   genetika   MeSH
• lidé MeSH
• mutageny toxicita   MeSH
• nádorové buněčné linie MeSH
• poškození DNA MeSH
• retroelementy účinky léků   genetika   MeSH
• ribozomální DNA genetika   metabolismus   MeSH
• stárnutí buněk účinky léků   genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH