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      Barrier-to-Autointegration Factor (BAF) involvement in prelamin A-related chromatin organization changes

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          Abstract

          Chromatin disorganization is one of the major alterations linked to prelamin A processing impairment. In this study we demonstrate that BAF is necessary to modulate prelamin A effects on chromatin structure. We show that when prelamin A and BAF cannot properly interact no prelamin A-dependent effects on chromatin occur; similar to what is observed in human Nestor Guillermo Progeria Syndrome cells harboring a BAF mutation, in HEK293 cells expressing a BAF mutant unable to bind prelamin A, or in siRNA mediated BAF-depleted HEK293 cells expressing prelamin A. BAF is necessary to induce histone trimethyl-H3K9 as well as HP1-alpha and LAP2-alpha nuclear relocalization in response to prelamin A accumulation. These findings are enforced by electron microscopy evaluations showing how the prelamin A-BAF interaction governs overall chromatin organization. Finally, we demonstrate that the LAP2-alpha nuclear localization defect observed in HGPS cells involves the progerin-BAF interaction, thus establishing a functional link between BAF and prelamin A pathological forms.

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          Most cited references40

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          Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks.

          Humans and animals undergo ageing, and although their primary cells undergo cellular senescence in culture, the relationship between these two processes is unclear. Here we show that gamma-H2AX foci (gamma-foci), which reveal DNA double-strand breaks (DSBs), accumulate in senescing human cell cultures and in ageing mice. They colocalize with DSB repair factors, but not significantly with telomeres. These cryptogenic gamma-foci remain after repair of radiation-induced gamma-foci, suggesting that they may represent DNA lesions with unrepairable DSBs. Thus, we conclude that accumulation of unrepairable DSBs may have a causal role in mammalian ageing.
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            Reduced histone biosynthesis and chromatin changes arising from a damage signal at telomeres

            During replicative aging of primary cells morphological transformations occur, the expression pattern is altered and chromatin changes globally. Here we show that chronic damage signals, likely caused by telomere processing, impact expression of histones and lead to their depletion. Interrogation of the abundance and cell cycle expression of histones and histone chaperones revealed defects in histone biosynthesis during replicative aging. Simultaneously, epigenetic marks were redistributed across the phases of the cell cycle and the DNA damage response (DDR) machinery was activated. The age-dependent reprogramming affected telomeric chromatin itself, which was progressively destabilized, resulting in a boost of the telomere associated DDR signal with each successive cell cycle. We propose a mechanism where changes in the structural and epigenetic integrity of telomeres impact core histones and their chaperones, enforcing a self-perpetuating pathway of global epigenetic changes that ultimately leads to senescence.
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              Elevated histone expression promotes life span extension.

              Changes to the chromatin structure accompany aging, but the molecular mechanisms underlying aging and the accompanying changes to the chromatin are unclear. Here, we report a mechanism whereby altering chromatin structure regulates life span. We show that normal aging is accompanied by a profound loss of histone proteins from the genome. Indeed, yeast lacking the histone chaperone Asf1 or acetylation of histone H3 on lysine 56 are short lived, and this appears to be at least partly due to their having decreased histone levels. Conversely, increasing the histone supply by inactivation of the histone information regulator (Hir) complex or overexpression of histones dramatically extends life span via a pathway that is distinct from previously known pathways of life span extension. This study indicates that maintenance of the fundamental chromatin structure is critical for slowing down the aging process and reveals that increasing the histone supply extends life span. Copyright © 2010 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                29 March 2016
                20 December 2015
                : 7
                : 13
                : 15662-15677
                Affiliations
                1 CNR-National Research Council of Italy, Institute of Molecular Genetics, Unit of Bologna, 40136 Bologna, Italy
                2 Laboratory of Musculoskeletal Cell Biology, IOR, 40136 Bologna, Italy
                3 Osteoarticolar Regeneration Laboratory, Rizzoli Orthopaedic Institute, 40136 Bologna, Italy
                4 Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, 40123 Bologna, Italy
                5 Department of Biochemistry and Molecular Biology, Medical Faculty, Oviedo University, 33006 Oviedo, Spain
                6 Max F. Perutz Laboratories, Medical University of Vienna, A-1030 Vienna, Austria
                Author notes
                Correspondence to: Cristina Capanni, ccapanni@ 123456area.bo.cnr.it
                Article
                6697
                10.18632/oncotarget.6697
                4941268
                26701887
                d2ef06d2-7c16-47e5-bd94-a4ef37860197
                Copyright: © 2016 Loi et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 25 August 2015
                : 21 November 2015
                Categories
                Research Paper

                Oncology & Radiotherapy
                prelamin a,barrier-to-autointegration factor,chromatin,hutchinson-gilford progeria syndrome,nestor-guillermo progeria

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