期刊
AGING CELL
卷 21, 期 2, 页码 -出版社
WILEY
DOI: 10.1111/acel.13554
关键词
aging; Drosophila; eye; neurons; photoreceptors; R-loop; transcription; visual
资金
- National Eye Institute of the NIH [1R21EY031024--01, 2R01EY024905]
The increase of R-loop levels is associated with decreased gene expression in aging neurons. Dysregulation of R-loop homeostasis leads to cellular dysfunction, increased cell death, and chronic disease onset. Top3 beta and nuclear-localized RNase H1 enhance positive light response during aging.
Age-related loss of cellular function and increased cell death are characteristic hallmarks of aging. While defects in gene expression and RNA metabolism have been linked with age-associated human neuropathies, it is not clear how the changes that occur in aging neurons contribute to loss of gene expression homeostasis. R-loops are RNA-DNA hybrids that typically form co-transcriptionally via annealing of the nascent RNA to the template DNA strand, displacing the non-template DNA strand. Dysregulation of R-loop homeostasis has been associated with both transcriptional impairment and genome instability. Importantly, a growing body of evidence links R-loop accumulation with cellular dysfunction, increased cell death, and chronic disease onset. Here, we characterized the R-loop landscape in aging Drosophila melanogaster photoreceptor neurons and showed that bulk R-loop levels increased with age. Further, genome-wide mapping of R-loops revealed that transcribed genes accumulated R-loops over gene bodies during aging, which correlated with decreased expression of long and highly expressed genes. Importantly, while photoreceptor-specific down-regulation of Top3 beta, a DNA/RNA topoisomerase associated with R-loop resolution, lead to decreased visual function, over-expression of Top3 beta or nuclear-localized RNase H1, which resolves R-loops, enhanced positive light response during aging. Together, our studies highlight the functional link between dysregulation of R-loop homeostasis, gene expression, and visual function during aging.
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