Healthy cells experience thousands of DNA lesions per day during normal cellular metabolism, and ionizing radiation and chemotherapeutic drugs rely on DNA damage to kill cancer cells. In response to such lesions, the DNA damage response (DDR) activates cell-cycle checkpoints, initiates DNA repair mechanisms, or promotes the clearance of irreparable cells. Work over the past decade has revealed broader influences of the DDR, involving inflammatory gene expression following unresolved DNA damage, and immune surveillance of damaged or mutated cells. Subcellular structures called micronuclei, containing broken fragments of DNA or whole chromosomes that have been isolated away from the rest of the genome, are now recognized as one mediator of DDR-associated immune recognition. Micronuclei can initiate pro-inflammatory signaling cascades, or massively degrade to invoke distinct forms of genomic instability. In this mini-review, we aim to provide an overview of the current evidence linking the DDR to activation of the immune response through micronuclei formation, identifying key areas of interest, open questions, and emerging implications.
Micronuclei (MN) are cytosolic bodies that sequester acentric fragments or mis-segregated chromosomes from the primary nucleus. Spontaneous rupture of the MN envelope allows recognition by the viral receptor cyclic GMP-AMP synthase (cGAS), initiating interferon signaling downstream of DNA damage. Here, we demonstrate that MN rupture is permissive but not sufficient for cGAS localization. Chromatin characteristics such as histone 3, lysine 79 dimethylation (H3K79me2) are present in the nucleus before DNA damage, retained in ruptured MN, and regulate cGAS recruitment. cGAS is further responsive to dynamic intra-MN processes occurring prior to rupture, including transcription. MN chromatin tethering via the nucleosome acidic patch is necessary for cGAS-dependent interferon signaling. Our data suggest that both damage-antecedent nuclear chromatin status and MN-contained chromatin organizational changes dictate cGAS recruitment and the magnitude of the cGAS-driven interferon cascade. Our work defines MN as integrative signaling hubs for the cellular response to genotoxic stress.
The endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) helps decide cell survival in diabetes. The alternative eukaryotic initiation factor 2A (EIF2A) has been proposed to mediate EIF2S1-independent translation during cellular stress and viral infection, but its role in cells is unknown. EIF2A abundance is high in human and mouse islets relative to other tissues, and both thapsigargin and palmitate significantly increased EIF2A mRNA and EIF2A protein levels in MIN6 cells, mouse islets and human islets. Knockdowns of EIF2A, the related factor EIF2D, or both EIF2A and EIF2D, were not sufficient to cause apoptosis. On the other hand, transient or stable EIF2A over-expression protected MIN6 cells, primary mouse islets, and human islets from ER stress-induced, caspase-3-dependent apoptosis. Mechanistically, EIF2A overexpression decreased ERN1 (also known as IRE1) expression in thapsigargin-treated MIN6 cells or human islets. In vivo, cell specific EIF2A viral overexpression reduced ER stress, improved insulin secretion, and abrogated hyperglycemia in Ins2Akita/WT mice. EIF2A overexpression significantly increased expression of genes involved in protein translation and reduced expression of pro-apoptotic genes (e.g. ALDH1A3). Remarkably, the decrease in global protein synthesis during UPR was prevented by EIF2A, despite ER stress-induced EIF2S1 phosphorylation. The protective effects of EIF2A were additive to those of ISRIB, a drug that counteracts the effects of EIF2S1 phosphorylation. Cells overexpressing EIF2A showed higher expression of translation factor EIF2B5, which may contribute to the lack of translational inhibition in these cells. We conclude that EIF2A is a novel target for cell protection and the circumvention of EIF2S1-mediated translational repression.
Introduction – The study of informatics is multidisciplinary in nature. The informatics course, HSC 310: Health Care Informatics (HSC 310), for undergraduate health sciences students at the Massachusetts College of Pharmacy and Health Sciences (MCPHS) is an example of a librarian-led, multidisciplinary team functioning within a totally online environment. Description – The development and design of the course HSC 310 is reviewed. Issues and challenges are discussed, as well as the benefits of interdisciplinary expertise in the learning environment. Outcomes – Because informatics is fundamentally interdisciplinary in nature, librarians, instructional designers, statisticians, nurses, pharmacists, and other professionals can learn from each other and strengthen the learning experience of students. The “matrix” of informatics explains how diverse types of information interact with, and impact on, each other. This knowledge is crucial to the understanding of information and its role in one's professional life. There was a journey taken in the design of the course, its evolution cumulating in its final online form. Our unique design was an informatics exercise in itself. Student feedback confirmed that, in addition to the course content, the online environment was a positive educational experience. Discussion – Librarian involvement in teaching informatics at MCPHS began with a National Library of Medicine (NLM) fellowship in informatics at Woods Hole, Massachusetts. This resulted in the library's first for-credit course offered totally in-class and included the participation of faculty from other disciplines. Successful collaboration with the College instructional designer was essential in moving this librarian-led course to a totally virtual environment. In addition, the teaming of librarians with other faculty resulted in two nursing-led, hybrid courses on our Boston and Manchester campuses. During the past two years, interdisciplinary teams have provided informatics instruction to the Boston campus within a totally online environment. This paper discusses one of those courses, HSC 310: Health Care Informatics. The topics discussed in the course and the virtual platform have both provided a valuable learning experience for faculty and students. Informatics is an area where varied disciplines can join to achieve common goals.
Catalogers have a unique challenge to overcome in demonstrating the value of their services: the better they are at performing their work-making collections accessible and enabling user discovery-the more invisible their efforts are to users and administrators. Catalogers must participate more actively in the broader discussion and demonstration of library value undertaken by their colleagues, but to do so requires a framework and a common vocabulary shared by non-catalogers.
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