Cytoplasmic synthesis of endogenous Alu complementary DNA via reverse transcription and implications in age-related macular degeneration

@article{Fukuda2021CytoplasmicSO,
  title={Cytoplasmic synthesis of endogenous Alu complementary DNA via reverse transcription and implications in age-related macular degeneration},
  author={Shinichi Fukuda and Akhil Varshney and Benjamin J. Fowler and Shao-Bin Wang and Siddharth Narendran and Kameshwari Ambati and Tetsuhiro Yasuma and Joseph Magagnoli and Hannah Leung and Shuichiro Hirahara and Yosuke Nagasaka and Reo Yasuma and Ivana Apicella and Felipe Pereira and Ryan D. Makin and Eamonn Magner and Xinan Liu and Jian Sun and Mo Wang and Kirstie L. Baker and Kenneth M. Marion and Xiwen Huang and Elmira Baghdasaryan and Meenakshi Ambati and Vidya L. Ambati and Akshat Pandey and Lekha Pandya and Tammy H. Cummings and Daipayan Banerjee and Peirong Huang and Praveen Yerramothu and Genrich V Tolstonog and Ulrike Held and Jennifer A. Erwin and Apu{\~a} C. M. Paquola and Joseph R Herdy and Yuichiro Ogura and Hiroko Terasaki and Tetsuro Oshika and Shaban Darwish and Ramendra K. Singh and Saghar Mozaffari and Deepak Bhattarai and Kyung Bo Kim and James W. Hardin and Charles L Bennett and David R Hinton and Timothy E. Hanson and Christian R{\"o}ver and Keykavous Parang and Nagaraj Kerur and Jinze Liu and Brian C. Werner and S. Scott Sutton and Srinivas R. Sadda and Gerald G. Schumann and Bradley D. Gelfand and Fred H. Gage and Jayakrishna Ambati},
  journal={Proceedings of the National Academy of Sciences},
  year={2021},
  volume={118}
}
Significance Alu elements, comprising more than 10% of the human genome, propagate via retrotransposition. This genomic expansion requires enzymatic activity of L1 that reverse transcribes Alu RNA into Alu cDNA in the nucleus. We report Alu also undergoes L1-mediated reverse transcription via self-priming in the cytoplasm independent of retrotransposition, providing evidence of human DNA synthesis in this cellular compartment. This newly discovered shunt molecule in the Alu replication cycle… Expand
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References

SHOWING 1-9 OF 9 REFERENCES
cGAS drives non-canonical inflammasome activation in age-related macular degeneration
TLDR
It is demonstrated that RPE degeneration in human-cell-culture and mouse models is driven by a noncanonical-inflammasome pathway that activates caspase-4, gasdermin D, interferon-β, and cGAS levels were elevated in the RPE in human eyes with geographic atrophy, and an unexpected role of cGas in responding to mobile-element transcripts is highlighted. Expand
Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition
TLDR
Long interspersed nuclear element (LINE-1; L1 hereafter) insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers. Expand
Structure of extrachromosomal circular DNAs containing both the Alu family of dispersed repetitive sequences and other regions of chromosomal DNA.
TLDR
Small polydisperse circular DNA isolated from the BSC-1 line of African Green monkey kidney cells was digested with the restriction endonuclease BamHI and cloned in bacteriophage lambda, and four of the 100 Alu-positive clones were characterized. Expand
A Clinical Metabolite of Azidothymidine Inhibits Experimental Choroidal Neovascularization and Retinal Pigmented Epithelium Degeneration
TLDR
GAZT possesses dual anti-inflammatory and anti-angiogenic properties and could be a viable treatment option for both forms of AMD. Expand
Repurposing anti-inflammasome NRTIs for improving insulin sensitivity and reducing type 2 diabetes development
TLDR
It is shown that the adjusted risk of incident diabetes is 33% lower in patients with NRTI exposure among 128,861 patients with HIV-1 or hepatitis B, and the possibility of repurposing an approved class of drugs for prevention of diabetes is suggested. Expand
Peptide amphiphile containing arginine and fatty acyl chains as molecular transporters.
TLDR
These studies suggest that PAs containing the appropriate sequence of amino acids, chain length, charge, and hydrophobicity can be used as cellular delivery tools for transporting drugs and biomolecules. Expand
Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis.
BACKGROUND Numerous population-based studies of age-related macular degeneration have been reported around the world, with the results of some studies suggesting racial or ethnic differences inExpand
Applying Causal Inference Methods in Psychiatric Epidemiology: A Review.
TLDR
Of the large family of statistical methods for causal inference, propensity scoring and marginal models are examined, which are best applied to samples with strong predictors of risk factor exposure and are important because it informs etiologic models and prevention efforts. Expand