L1 retrotransposons are an abundant class of transposable elements which pose a threat to genome stability and may play a role in age-related pathologies such as cancer. Recent evidence indicates that L1s become more active in somatic tissues during the course of aging; the mechanisms underlying this phenomenon remain unknown, however. Here we report that the longevity regulating protein, SIRT6, is a powerful repressor of L1 activity. Specifically, SIRT6 binds to the 5′UTR of L1 loci, where it mono-ADP ribosylates the nuclear corepressor protein, KAP1, and facilitates KAP1 interaction with the heterochromatin factor, HP1α, thereby contributing to the packaging of L1 elements into transcriptionally repressive heterochromatin. During the course of aging, and also in response to DNA damage, however, we find that SIRT6 is depleted from L1 loci, allowing for the activation of these previously silenced retroelements.
Facioscapulohumeral dystrophy (FSHD) is caused by the mis-expression of DUX4 in skeletal muscle cells. DUX4 is a transcription factor that activates genes normally associated with stem cell biology and its mis-expression in FSHD cells results in apoptosis. To identify genes and pathways necessary for DUX4-mediated apoptosis, we performed an siRNA screen in an RD rhabdomyosarcoma cell line with an inducible DUX4 transgene. Our screen identified components of the MYC-mediated apoptotic pathway and the double-stranded RNA (dsRNA) innate immune response pathway as mediators of DUX4-induced apoptosis. Further investigation revealed that DUX4 expression led to increased MYC mRNA, accumulation of nuclear dsRNA foci, and activation of the dsRNA response pathway in both RD cells and human myoblasts. Nuclear dsRNA foci were associated with aggregation of the exon junction complex component EIF4A3. The elevation of MYC mRNA, dsRNA accumulation, and EIF4A3 nuclear aggregates in FSHD muscle cells suggest that these processes might contribute to FSHD pathophysiology.
SUMMARY
The accumulation of damage caused by oxidative stress has been linked to aging and to the etiology of numerous age-related diseases. The longevity gene, sirtuin 6 (SIRT6), promotes genome stability by facilitating DNA repair, especially under oxidative stress conditions. Here we uncover the mechanism by which SIRT6 is activated by oxidative stress to promote DNA double-strand break (DSB) repair. We show that the stress-activated protein kinase, c-Jun N-terminal kinase (JNK), phosphorylates SIRT6 on serine 10 in response to oxidative stress. This post-translational modification facilitates the mobilization of SIRT6 to DNA damage sites and is required for efficient recruitment of poly (ADP-ribose) polymerase 1 (PARP1) to DNA break sites and for efficient repair of DSBs. Our results demonstrate a post-translational mechanism regulating SIRT6, and they provide the link between oxidative stress signaling and DNA repair pathways that may be critical for hormetic response and longevity assurance.
As the average human lifespan lengthens, the impact of neurodegenerative disease increases, both on the individual suffering neurodegeneration and on the community that supports those individuals. Studies aimed at understanding the mechanisms of neurodegeneration have relied heavily on observational studies of humans and experimental studies in animals, such as mice, in which aspects of brain structure and function can be manipulated to target mechanistic steps. An animal model whose brain is structurally closer to the human brain, that lives much longer than rodents, and whose husbandry is practical may be valuable for mechanistic studies that cannot readily be conducted in rodents. To demonstrate that the long-lived Seba’s short-tailed fruit bat, Carollia perspicillata, may fit this role, we used immunohistochemical labeling for NeuN and three calcium-binding proteins, calretinin, parvalbumin, and calbindin, to define hippocampal formation anatomy. Our findings demonstrate patterns of principal neuron organization that resemble primate and human hippocampal formation and patterns of calcium-binding protein distribution that help to define subregional boundaries. Importantly, we present evidence for a clear prosubiculum in the bat brain that resembles primate prosubiculum. Based on the similarities between bat and human hippocampal formation anatomy, we suggest that Carollia has unique advantages for the study of brain aging and neurodegeneration. A captive colony of Carollia allows age tracking, diet and environment control, pharmacological manipulation, and access to behavioral, physiological, anatomical, and molecular evaluation.
This study aims to assess prospectively whether there is an association between frequencies of upper respiratory tract infections (URTI) or asthma in early childhood and failed otoacoustic emission (OAE) screenings later in life. There are no clear recommendations for hearing testing following acute otitis media (AOM) infection. This is a retrospective, practice based chart review. Participants from a primary care setting were 517 pre-adolescent and adolescent children (49.9% female) (ages 10–21; mean, 15 y/o), who had presented with at least one specific bacterial URTI (AOM, Group A Streptococcus (GAS) tonsillitis, or Influenza) during childhood. Hearing testing was recorded incidentally at all subsequent routine health care maintenance visits (OAE hearing screen). Simple linear regression analyses were performed using R (v3.4.4). We found that number of episodes of AOM infections strongly correlated with number of failed OAE screenings later in life (F = 76.37;
P
= <0.001; R
2
= 0.1279), while GAS (F = 1.859;
P
= 0.1733; R
2
= 0.0016) or Influenza infection (F = 2.624;
P
= 0.1059; R
2
= 0.0031) were not associated with failed OAE screening. Correlation between number of AOM infections and number of failed OAE screenings was not strengthened by presence of asthma. This study found evidence of an association between childhood history of AOM and failed OAE screenings in adolescence. Since this population may be at a higher risk for developing permanent or fluctuating hearing losses, further studies to clarify indications and timing of standard audiological testing among these children should be considered.
RATIONALE: CD4+IL-4+ T cells are required for human and murine IgE responses. We reported that CD4+ T cells and CD8+CD60+ T cells and six cytokines 4,6,10,12,IFNa,IFNg) are required for induction of ragweed specific memory IgE responses. Antigen cleaves complement and human CD4+ T cells express receptors for CSP. Receptors for CSP C3a and C5a on CD8+CD60+ T cells have not been reported. METHODS: CD4+CD3+ and CD8+CD60+CD45RO6CD45RA6IL-46IFNg6 T cells in blood of serum IgE+ (fluoroimmunoassay) ragweed sensitized (RS) and IgE-nonallergic humans expressing receptors for CSP C3a and C5a (CD88) (n52-3/group) were determined by flow cytometry. Data expressed as mean % total lymphocytes and % subset. RESULTS: Blood of IgE+ RS humans contained increased numbers of CD4+ and CD8+CD60+ T cells expressing receptors for C3a (36, 85%, respectively), compared with IgE-nonallergic humans (16, 36%, respectively). Further, in IgE+, but not IgE-humans, both T cell subsets expressed greatly increased C3a receptors/cell (MESF). In IgE+ humans, virtually all CD8+CD60+ T cells were CD45RO+CD45RA-and IL-4+IFNg-; in IgE-humans they were virtually all IL-4-, with CD45RA+ cells predominating. Neither CD4+ nor CD8+CD606 T cells of either IgE+ or IgE-humans expressed receptors for CSP C5a (CD88) (<1%). CONCLUSIONS: The presence of receptors for C3a on CD4+ and CD8+CD60+CD45RO+ IL-4+ T cells required for induction of ragweed specific memory IgE responses suggests that C3a may play an important role in induction of these responses.
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