{"title":"On the interface of aging, cancer, and neurodegeneration with SIRT6 and L1 retrotransposon protein interaction network","authors":"Jarmila Nahálková","doi":"10.1016/j.arr.2024.102496","DOIUrl":null,"url":null,"abstract":"<div><div>Roles of the sirtuins in aging and longevity appear related to their evolutionarily conserved functions as retroviral-restriction factors. Retrotransposons also promote the aging process, which can be reversed by the inhibition of their activity. SIRT6 can functionally limit the mutation activity of LINE-1 (L1), a retrotransposon causing cancerogenesis-linked mutations accumulating during aging. Here, an overview of the molecular mechanisms of the controlling effects was created by the pathway enrichment and gene function prediction analysis of a protein interaction network of SIRT6 and L1 retrotransposon proteins L1 ORF1p, and L1 ORF2p. The L1-SIRT6 interaction network is enriched in pathways and nodes associated with RNA quality control, DNA damage response, tumor-related and retrotransposon activity-suppressing functions. The analysis also highlighted sumoylation, which controls protein-protein interactions, subcellular localization, and other post-translational modifications; DNA IR Damage and Cellular Response via ATR, and Hallmark Myc Targets V1, which scores are a measure of tumor aggressiveness. The protein node prioritization analysis emphasized the functions of tumor suppressors p53, PARP1, BRCA1, and BRCA2 having L1 retrotransposon limiting activity; tumor promoters EIF4A3, HNRNPA1, HNRNPH1, DDX5; and antiviral innate immunity regulators DDX39A and DDX23. The outline of the regulatory mechanisms involved in L1 retrotransposition with a focus on the prioritized nodes is here demonstrated in detail. Furthermore, a model establishing functional links between HIV infection, L1 retrotransposition, SIRT6, and cancer development is also presented. Finally, L1-SIRT6 subnetwork SIRT6-PARP1-BRCA1/BRCA2-TRIM28-PIN1-p53 was constructed, where all nodes possess L1 retrotransposon activity-limiting activity and together represent candidates for multitarget control.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"101 ","pages":"Article 102496"},"PeriodicalIF":12.5000,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Ageing Research Reviews","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1568163724003143","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Roles of the sirtuins in aging and longevity appear related to their evolutionarily conserved functions as retroviral-restriction factors. Retrotransposons also promote the aging process, which can be reversed by the inhibition of their activity. SIRT6 can functionally limit the mutation activity of LINE-1 (L1), a retrotransposon causing cancerogenesis-linked mutations accumulating during aging. Here, an overview of the molecular mechanisms of the controlling effects was created by the pathway enrichment and gene function prediction analysis of a protein interaction network of SIRT6 and L1 retrotransposon proteins L1 ORF1p, and L1 ORF2p. The L1-SIRT6 interaction network is enriched in pathways and nodes associated with RNA quality control, DNA damage response, tumor-related and retrotransposon activity-suppressing functions. The analysis also highlighted sumoylation, which controls protein-protein interactions, subcellular localization, and other post-translational modifications; DNA IR Damage and Cellular Response via ATR, and Hallmark Myc Targets V1, which scores are a measure of tumor aggressiveness. The protein node prioritization analysis emphasized the functions of tumor suppressors p53, PARP1, BRCA1, and BRCA2 having L1 retrotransposon limiting activity; tumor promoters EIF4A3, HNRNPA1, HNRNPH1, DDX5; and antiviral innate immunity regulators DDX39A and DDX23. The outline of the regulatory mechanisms involved in L1 retrotransposition with a focus on the prioritized nodes is here demonstrated in detail. Furthermore, a model establishing functional links between HIV infection, L1 retrotransposition, SIRT6, and cancer development is also presented. Finally, L1-SIRT6 subnetwork SIRT6-PARP1-BRCA1/BRCA2-TRIM28-PIN1-p53 was constructed, where all nodes possess L1 retrotransposon activity-limiting activity and together represent candidates for multitarget control.
期刊介绍:
With the rise in average human life expectancy, the impact of ageing and age-related diseases on our society has become increasingly significant. Ageing research is now a focal point for numerous laboratories, encompassing leaders in genetics, molecular and cellular biology, biochemistry, and behavior. Ageing Research Reviews (ARR) serves as a cornerstone in this field, addressing emerging trends.
ARR aims to fill a substantial gap by providing critical reviews and viewpoints on evolving discoveries concerning the mechanisms of ageing and age-related diseases. The rapid progress in understanding the mechanisms controlling cellular proliferation, differentiation, and survival is unveiling new insights into the regulation of ageing. From telomerase to stem cells, and from energy to oxyradical metabolism, we are witnessing an exciting era in the multidisciplinary field of ageing research.
The journal explores the cellular and molecular foundations of interventions that extend lifespan, such as caloric restriction. It identifies the underpinnings of manipulations that extend lifespan, shedding light on novel approaches for preventing age-related diseases. ARR publishes articles on focused topics selected from the expansive field of ageing research, with a particular emphasis on the cellular and molecular mechanisms of the aging process. This includes age-related diseases like cancer, cardiovascular disease, diabetes, and neurodegenerative disorders. The journal also covers applications of basic ageing research to lifespan extension and disease prevention, offering a comprehensive platform for advancing our understanding of this critical field.