[en] Histone deacetylase plays a role in a wide range of cellular processes including cell proliferation, senescence and apoptosis, thereby regulating cellular stress response and lifespan. HDAC is believed to delay the aging process by regulating metabolism and endocrine signaling and protecting against age related diseases. The eukaryotic initiation factor 2-alpha (eIF2) is central to translation control in response to cellular stress. Translation is controlled by different extra and intra-cellular stimuli, such as nutrients, growth factors, hormones and stress signals. The inhibition of protein synthesis, as a result of eIF2 phosphorylation occurs very rapidly following exposure to stress. In this paper, our results show that depletion of HDAC remarkably increases eIF2 phosphorlyation in stress condition

[en] A principal therapeutic intent of exposing a tumor to ionizing radiation is to produce irreversible DNA damage in the tumor cells while sparing the around normal tissues involved. The fast kinetics of cell cycling in the tumor cells decreases the desired-effect and requires reduction in overall treatment time to achieve destruction of the malignant cells with minimal adverse effects on the surrounding non-malignant tissue. The access of molecular cell cycle-targeted therapy may represent a supplement to accelerated fractionation regimens in improving the therapeutic index. Complete depletion of Mad2 protein levels induces mitotic failure, multi-nucleation, and apoptosis in tumor cell utilizing RNA interference. CMT2 counteracts the function of Mad2 and is required for the silencing of the spindle checkpoint. In this study, we identified that CMT2 induces tumor cell death and permanent growth arrest

[en] Sir2 maintains genomic stability in multiple ways in yeast. As a NAD⁺-dependent histone deacetylase, Sir2 has been reported to control chromatin silencing. In both budding yeast and Drosophila, overexpression of Sir2 extends life span. Previous reports have also demonstrated that Sir2 participate at DNA damage repair. A protein complex containing Sir2 has been reported to translocate to DNA double-strand breaks. Following DNA damage response, SIRT1 deacetylates p53 protein and attenuates its ability as a transcription factor. Consequently, SIRT1 over-expression increases cell survival under DNA damage inducing conditions. These previous observations mean a possibility that signals generated during the process of DNA repair are delivered through SIRT1 to acetylated p53. We present herein functional evidence for the involvement of SIRT1 in DNA repair response to radiation. In addition, this modulation of DNA repair activity may be connected to deacetylation of MRN proteins

[en] A telomere is a region of repetitive DNA at the end of chromosomes. They protect a cell's chromosomes from fusing with each other or rearranging and so cells are normally destroyed when their telomeres are consumed. Most normal somatic cells lose telomeric repeats after each cell division. Telomeric shortening in humans can induce replicative senescence which blocks cell division. This mechanism appears to prevent genomic instability by limiting the number of cell divisions. Telomerase is an attractive molecular target, since its activity has been found in more than 85% of human cancers. Combination therapy with chemotherapeutic agent is superior to single in overall response rate and progression free survival. In this study, we showed that telomerase null cells are more hypersensitive by paclitaxel treatment than at wild type cells

[en] Highlights: ► SIRT1 serves to retain GAPDH in the cytosol, preventing GAPDH nuclear translocation. ► When SIRT1 is depleted, GAPDH translocation occurs even in the absence of stress. ► Upon irradiation, SIRT1 interacts with GAPDH. ► SIRT1 prevents irradiation-induced nuclear translocation of GAPDH. ► SIRT1 presence rather than activity is essential for inhibiting GAPDH translocation. -- Abstract: Upon apoptotic stimulation, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a cytosolic enzyme normally active in glycolysis, translocates into the nucleus and activates an apoptotic cascade therein. In the present work, we show that SIRT1 prevents nuclear translocation of GAPDH via interaction with GAPDH. SIRT1 depletion triggered nuclear translocation of cytosolic GAPDH even in the absence of apoptotic stress. Such translocation was not, however, observed when SIRT1 enzymatic activity was inhibited, indicating that SIRT1 protein per se, rather than the deacetylase activity of the protein, is required to inhibit GAPDH translocation. Upon irradiation, SIRT1 prevented irradiation-induced nuclear translocation of GAPDH, accompanied by interaction of SIRT1 and GAPDH. Thus, SIRT1 functions to retain GAPDH in the cytosol, protecting the enzyme from nuclear translocation via interaction with these two proteins. This serves as a mechanism whereby SIRT1 regulates cell survival upon induction of apoptotic stress by means that include irradiation.

[en] Highlights: ► Under conditions of telomere erosion, cells become extremely sensitive to H₂O₂. ► Chromosomal regions adjacent to telomeres are cleaved by H₂O₂ under such conditions. ► H₂O₂ thus causes multichromosomal fusions and generation of small chromosomal fragments. ► N-acetylcysteine prevents H₂O₂-induced chromosomal aberrations. -- Abstract: During genotoxic stress, reactive oxygen species hydrogen peroxide (H₂O₂) is a prime mediator of the DNA damage response. Telomeres function both to assist in DNA damage repair and to inhibit chromosomal end-to-end fusion. Here, we show that telomere dysfunction renders cells susceptible to H₂O₂, via generation of multichromosomal fusion and chromosomal fragments. H₂O₂ caused formation of multichromosomal end-to-end fusions involving more than three chromosomes, preferentially when telomeres were erosive. Interestingly, extensive chromosomal fragmentation (yielding small-sized fragments) occurred only in cells exhibiting such multichromosomal fusions. Telomeres were absent from fusion points, being rather present in the small fragments, indicating that H₂O₂ cleaves chromosomal regions adjacent to telomeres. Restoration of telomere function or addition of the antioxidant N-acetylcysteine prevented development of chromosomal aberrations and rescued the observed hypersensitivity to H₂O₂. Thus, chromosomal regions adjacent to telomeres become sensitive to reactive oxygen species hydrogen peroxide when telomeres are dysfunctional, and are cleaved to produce multichromosomal fusions and small chromosomal fragments bearing the telomeres.