On the interface of aging, cancer, and neurodegeneration with SIRT6 and L1 retrotransposon protein interaction network

IF 12.5 1区 医学 Q1 CELL BIOLOGY
Jarmila Nahálková
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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.
用 SIRT6 和 L1 逆转录转座子蛋白相互作用网络探讨衰老、癌症和神经退行性病变的界面。
sirtuins在衰老和长寿中的作用似乎与它们作为逆转录病毒限制因子的进化保守功能有关。逆转录病毒也会促进衰老过程,而抑制逆转录病毒的活性可以逆转衰老过程。SIRT6可以在功能上限制LINE-1(L1)的突变活性,LINE-1是一种逆转录转座子,会在衰老过程中导致与癌症发生相关的突变累积。本文通过对SIRT6与L1逆转录转座子蛋白L1 ORF1p和L1 ORF2p的蛋白相互作用网络进行通路富集和基因功能预测分析,概述了其控制作用的分子机制。L1-SIRT6相互作用网络富含与RNA质量控制、DNA损伤应答、肿瘤相关和抑制逆转录转座子活性功能相关的通路和节点。分析还突出了苏木酰化(控制蛋白质-蛋白质相互作用、亚细胞定位和其他翻译后修饰)、DNA IR损伤和通过ATR的细胞反应以及Hallmark Myc Targets V1(其得分是衡量肿瘤侵袭性的指标)。蛋白质节点优先级分析强调了具有 L1 逆转录子限制活性的肿瘤抑制因子 p53、PARP1、BRCA1 和 BRCA2;肿瘤启动子 EIF4A3、HNRNPA1、HNRNPH1、DDX5;以及抗病毒先天免疫调节因子 DDX39A 和 DDX23 的功能。本文以优先节点为重点,详细展示了 L1 逆转录过程中的调控机制。此外,还介绍了一个模型,该模型建立了 HIV 感染、L1 逆转录、SIRT6 和癌症发展之间的功能联系。最后,构建了 L1-SIRT6 子网络 SIRT6-PARP1-BRCA1/BRCA2-TRIM28-PIN1-p53,其中所有节点都具有 L1 逆转录转座子的限制活性,共同代表了多目标控制的候选者。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Ageing Research Reviews
Ageing Research Reviews 医学-老年医学
CiteScore
19.80
自引率
2.30%
发文量
216
审稿时长
55 days
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.
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