RESUMEN
The endosymbiosis of mitochondrial ancestors resulted in the transfer of genetic material on an evolutionary scale for eukaryotic species. A new study in PLOS Biology expands this to the genome of somatic cells within individuals and highlights its correlation with aging and disease.
Asunto(s)
Mitocondrias , Simbiosis , Simbiosis/genética , Mitocondrias/genética , Mitocondrias/metabolismo , Humanos , Animales , Envejecimiento/genética , Envejecimiento/fisiología , Genómica/métodos , Genoma/genética , Genoma MitocondrialRESUMEN
Schizosaccharomyces pombe delays entry into mitosis following G2 microtubule damage. This pathway is dependent on Rad26ATRIP, the regulatory subunit of the Rad26ATRIP/Rad3ATR DNA damage response (DDR) complex. However, this G2 microtubule damage response pathway acts independently of the G2 DNA damage checkpoint pathway. To identify other proteins in this G2 microtubule damage pathway, we previously screened a cDNA overexpression library for genes that rescued the sensitivity of rad26Δ cells to the microtubule poison thiabendazole. A partial cDNA fragment encoding only the C-terminal regulatory region of the microtubule bundling protein Ase1 PRC1 was isolated. This fragment lacks the Ase1PRC1 dimerization and microtubule binding domains and retains the conserved C-terminal unstructured regulatory region. Here, we report that ase1Δ cells fail to delay entry into mitosis following G2 microtubule damage. Microscopy revealed that Rad26ATRIP foci localized alongside Ase1PRC1 filaments, although we suggest that this is related to microtubule-dependent double strand break mobility that facilitates homologous recombination events. Indeed, we report that the DNA repair protein Rad52 co-localizes with Rad26ATRIP at these foci, and that localization of Rad26ATRIP to these foci depends on a Rad26ATRIP N-terminal region containing a checkpoint recruitment domain. To our knowledge, this is the first report implicating Ase1PRC1 in regulation of the G2/M transition.
RESUMEN
Background: Many humans suffering with chronic neuropathic pain have no objective evidence of an etiological lesion or disease. Frequently their persistent pain occurs after the healing of a soft tissue injury. Based on clinical observations over time, our hypothesis was that after an injury in mammals the process of tissue repair could cause chronic neural pain. Our objectives were to create the delayed onset of neuropathic pain in rats with minimal nerve trauma using a physiologic hydrogel, and characterize the rats' responses to known analgesics and a targeted biologic. Methods: In mature male Sprague Dawley rats (age 9.5 months) a percutaneous implant of tissue-derived hydrogel was placed in the musculofascial tunnel of the distal tibial nerve. Subcutaneous morphine (3 mg/kg), celecoxib (10 mg/kg), gabapentin (25 mg/kg) and duloxetine (10 mg/kg) were each screened in the model three times each over 5 months after pain behaviors developed. Sham and control groups were used in all screenings. A pilot study followed in which recombinant human erythropoietin (200 units) was injected by the GEL™ neural procedure site. Results: The GEL group gradually developed mechanical hypersensitivity lasting months. Morphine, initially effective, had less analgesia over time. Celecoxib produced no analgesia, while gabapentin and duloxetine at low doses demonstrated profound analgesia at all times tested. The injected erythropoietin markedly decreased bilateral pain behavior that had been present for over 4 months, p ≤ 0.001. Histology of the GEL group tibial nerve revealed a site of focal neural remodeling, with neural regeneration, as found in nerve biopsies of patients with neuropathic pain. Conclusion: The refined NeuroDigm GEL™ model induces a neural response resulting in robust neuropathic pain behavior. The analgesic responses in this model reflect known responses of humans with neuropathic pain. The targeted recombinant human erythropoietin at the ectopic neural lesion appears to alleviate the persistent pain behavior in the GEL™ model rodents.