2019 Articles

Mariotti M, Salinas G, Gabaldón T, Gladyshev VN. (2019) Utilization of selenocysteine in early-branching fungal phyla. Nat Microbiol. 4(5), 759-765.

AbstractSelenoproteins are a diverse group of proteins containing selenocysteine (Sec)-the twenty-first amino acid-incorporated during translation via a unique recoding mechanism1,2. Selenoproteins fulfil essential roles in many organisms1, yet are not ubiquitous across the tree of life3-7. In particular, fungi were deemed devoid of selenoproteins4,5,8. However, we show here that Sec is utilized by nine species belonging to diverse early-branching fungal phyla, as evidenced by the genomic presence of both Sec machinery and selenoproteins. Most fungal selenoproteins lack consensus Sec recoding signals (SECIS elements9) but exhibit other RNA structures, suggesting altered mechanisms of Sec insertion in fungi. Phylogenetic analyses support a scenario of vertical inheritance of the Sec trait within eukaryotes and fungi. Sec was then lost in numerous independent events in various fungal lineages. Notably, Sec was lost at the base of Dikarya, resulting in the absence of selenoproteins in Saccharomyces cerevisiae and other well-studied fungi. Our results indicate that, despite scattered occurrence, selenoproteins are found in all kingdoms of life. More Information

Simon M, Van Meter M, Ablaeva J, Ke Z, Gonzalez RS, Taguchi T, De Cecco M, Leonova KI, Kogan V, Helfand SL, Neretti N, Roichman A, Cohen HY, Meer MV, Gladyshev VN, Antoch MP, Gudkov AV, Sedivy JM, Seluanov A, Gorbunova V. (2019) LINE1 Derepression in Aged Wild-Type and SIRT6-Deficient Mice Drives Inflammation. Cell Metab. 29, e5.

AbstractMice deficient for SIRT6 exhibit a severely shortened lifespan, growth retardation, and highly elevated LINE1 (L1) activity. Here we report that SIRT6-deficient cells and tissues accumulate abundant cytoplasmic L1 cDNA, which triggers strong type I interferon response via activation of cGAS. Remarkably, nucleoside reverse-transcriptase inhibitors (NRTIs), which inhibit L1 retrotransposition, significantly improved health and lifespan of SIRT6 knockout mice and completely rescued type I interferon response. In tissue culture, inhibition of L1 with siRNA or NRTIs abrogated type I interferon response, in addition to a significant reduction of DNA damage markers. These results indicate that L1 activation contributes to the pathologies of SIRT6 knockout mice. Similarly, L1 transcription, cytoplasmic cDNA copy number, and type I interferons were elevated in the wild-type aged mice. As sterile inflammation is a hallmark of aging, we propose that modulating L1 activity may be an important strategy for attenuating age-related pathologies. More Information

Egorov AA, Sakharova EA, Anisimova AS, Dmitriev SE, Gladyshev VN, Kulakovskiy IV. (2019) svis4get: a simple visualization tool for genomic tracks from sequencing experiments. BMC Bioinformatics. 20, 113.

AbstractHigh-throughput sequencing often provides a foundation for experimental analyses in the life sciences. For many such methods, an intermediate layer of bioinformatics data analysis is the genomic signal track constructed by short read mapping to a particular genome assembly. There are many software tools to visualize genomic tracks in a web browser or with a stand-alone graphical user interface. However, there are only few command-line applications suitable for automated usage or production of publication-ready visualizations. More Information

O’Connell AE, Gerashchenko MV, O’Donohue MF, Rosen SM, Huntzinger E, Gleeson D, Galli A, Ryder E, Cao S, Murphy Q, Kazerounian S, Morton SU, Schmitz-Abe K, Gladyshev VN, Gleizes PE, Séraphin B, Agrawal PB. (2019) Mammalian Hbs1L deficiency causes congenital anomalies and developmental delay associated with Pelota depletion and 80S monosome accumulation. PLoS Genet. 15, e1007917.

AbstractHbs1 has been established as a central component of the cell’s translational quality control pathways in both yeast and prokaryotic models; however, the functional characteristics of its human ortholog (Hbs1L) have not been well-defined. We recently reported a novel human phenotype resulting from a mutation in the critical coding region of the HBS1L gene characterized by facial dysmorphism, severe growth restriction, axial hypotonia, global developmental delay and retinal pigmentary deposits. Here we further characterize downstream effects of the human HBS1L mutation. HBS1L has three transcripts in humans, and RT-PCR demonstrated reduced mRNA levels corresponding with transcripts V1 and V2 whereas V3 expression was unchanged. Western blot analyses revealed Hbs1L protein was absent in the patient cells. Additionally, polysome profiling revealed an abnormal aggregation of 80S monosomes in patient cells under baseline conditions. RNA and ribosomal sequencing demonstrated an increased translation efficiency of ribosomal RNA in Hbs1L-deficient fibroblasts, suggesting that there may be a compensatory increase in ribosome translation to accommodate the increased 80S monosome levels. This enhanced translation was accompanied by upregulation of mTOR and 4-EBP protein expression, suggesting an mTOR-dependent phenomenon. Furthermore, lack of Hbs1L caused depletion of Pelota protein in both patient cells and mouse tissues, while PELO mRNA levels were unaffected. Inhibition of proteasomal function partially restored Pelota expression in human Hbs1L-deficient cells. We also describe a mouse model harboring a knockdown mutation in the murine Hbs1l gene that shared several of the phenotypic elements observed in the Hbs1L-deficient human including facial dysmorphism, growth restriction and retinal deposits. The Hbs1lKO mice similarly demonstrate diminished Pelota levels that were rescued by proteasome inhibition. More Information

Tian X, Firsanov D, Zhang Z, Cheng Y, Luo L, Tombline G, Tan R, Simon M, Henderson S, Steffan J, Goldfarb A, Tam J, Zheng K, Cornwell A, Johnson A, Yang JN, Mao Z, Manta B, Dang W, Zhang Z, Vijg J, Wolfe A, Moody K, Kennedy BK, Bohmann D, Gladyshev VN, Seluanov, Gorbunova V. (2019) SIRT6 Is Responsible for More Efficient DNA Double-Strand Break Repair in Long-Lived Species. Cell. 177, 622-638.e22.

AbstractDNA repair has been hypothesized to be a longevity determinant, but the evidence for it is based largely on accelerated aging phenotypes of DNA repair mutants. Here, using a panel of 18 rodent species with diverse lifespans, we show that more robust DNA double-strand break (DSB) repair, but not nucleotide excision repair (NER), coevolves with longevity. Evolution of NER, unlike DSB, is shaped primarily by sunlight exposure. We further show that the capacity of the SIRT6 protein to promote DSB repair accounts for a major part of the variation in DSB repair efficacy between short- and long-lived species. We dissected the molecular differences between a weak (mouse) and a strong (beaver) SIRT6 protein and identified five amino acid residues that are fully responsible for their differential activities. Our findings demonstrate that DSB repair and SIRT6 have been optimized during the evolution of longevity, which provides new targets for anti-aging interventions. More Information

Ogrodnik M, Salmonowicz H, Gladyshev VN. (2019) Integrating cellular senescence with the concept of damage accumulation in aging: Relevance for clearance of senescent cells. Agin Cell. 18, e12841.

AbstractUnderstanding the aging process and ways to manipulate it is of major importance for biology and medicine. Among the many aging theories advanced over the years, the concept most consistent with experimental evidence posits the buildup of numerous forms of molecular damage as a foundation of the aging process. Here, we discuss that this concept integrates well with recent findings on cellular senescence, offering a novel view on the role of senescence in aging and age-related disease. Cellular senescence has a well-established role in cellular aging, but its impact on the rate of organismal aging is less defined. One of the most prominent features of cellular senescence is its association with macromolecular damage. The relationship between cell senescence and damage concerns both damage as a molecular signal of senescence induction and accelerated accumulation of damage in senescent cells. We describe the origin, regulatory mechanisms, and relevance of various damage forms in senescent cells. This view on senescent cells as carriers and inducers of damage puts new light on senescence, considering it as a significant contributor to the rise in organismal damage. Applying these ideas, we critically examine current evidence for a role of cellular senescence in aging and age-related diseases. We also discuss the differential impact of longevity interventions on senescence burden and other types of age-related damage. Finally, we propose a model on the role of aging-related damage accumulation and the rate of aging observed upon senescent cell clearance. More Information

Galkin F, Zhang B, Dmitriev SE, Gladyshev VN. (2019) Reversibility of irreversible aging. Ageing Res Rev. 49, 104-114.

AbstractMost multicellular organisms are known to age, due to accumulation of damage and other deleterious changes over time. These changes are often irreversible, as organisms, humans included, evolved fully differentiated, irreplaceable cells (e.g. neurons) and structures (e.g. skeleton). Hence, deterioration or loss of at least some cells and structures should lead to inevitable aging of these organisms. Yet, some cells may escape this fate: adult somatic cells may be converted to partially reprogrammed cells or induced pluripotent stem cells (iPSCs). By their nature, iPSCs are the cells representing the early stages of life, indicating a possibility of reversing the age of cells within the organism. Reprogramming strategies may be accomplished both in vitro and in vivo, offering opportunities for rejuvenation in the context of whole organisms. Similarly, older organs may be replaced with the younger ones prepared ex vivo, or grown within other organisms or even other species. How could the irreversibility of aging of some parts of the organism be reconciled with the putative reversal of aging of the other parts of the same organism? Resolution of this question holds promise for dramatically extending lifespan, which is currently not possible with traditional genetic, dietary and pharmacological approaches. Critical issues in this challenge are the nature of aging, relationship between aging of an organism and aging of its parts, relationship between cell dedifferentiation and rejuvenation, and increased risk of cancer that goes hand in hand with rejuvenation approaches. More Information