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https://www.readbyqxmd.com/read/28515154/progerin-sequestration-of-pcna-promotes-replication-fork-collapse-and-mislocalization-of-xpa-in-laminopathy-related-progeroid-syndromes
#1
Benjamin A Hilton, Ji Liu, Brian M Cartwright, Yiyong Liu, Maya Breitman, Youjie Wang, Rowdy Jones, Hui Tang, Antonio Rusinol, Phillip R Musich, Yue Zou
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder that is caused by a point mutation in the LMNA gene resulting in production of a truncated farnesylated-prelamin A protein (progerin). We previously reported that XPA mislocalized to the progerin-induced DNA double-strand break (DSB) sites, blocking DSB repair, which led to DSB accumulation, DNA damage responses, and early replication arrest in HGPS. In this study, the XPA mislocalization to DSBs occurred at stalled or collapsed replication forks, concurrent with a significant loss of PCNA at the forks, whereas PCNA efficiently bound to progerin...
May 17, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28483909/progerin-induced-replication-stress-facilitates-premature-senescence-in-hutchinson-gilford-progeria-syndrome
#2
Keith Wheaton, Denise Campuzano, Weili Ma, Michal Sheinis, Brandon Ho, Grant W Brown, Samuel Benchimol
Hutchinson-Gilford progeria syndrome (HGPS) is caused by a mutation in LMNA that produces an aberrant lamin A protein, progerin. The accumulation of progerin in HGPS cells leads to an aberrant nuclear morphology, genetic instability and p53-dependent premature senescence. How p53 is activated in response to progerin production is unknown. Here, we show that young, cycling HGPS fibroblasts, exhibit chronic DNA damage primarily in S phase as well as delayed replication fork progression. We demonstrate that progerin binds to PCNA altering its distribution away from replicating DNA in HGPS cells leading to γH2AX formation, ATR activation and RPA Ser33 phosphorylation...
May 8, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28477268/expression-of-progerin-does-not-result-in-an-increased-mutation-rate
#3
Emmanuelle Deniaud, Charlene Lemaître, Shelagh Boyle, Wendy A Bickmore
In the premature ageing disease Hutchinson-Gilford progeria syndrome (HGPS), the underlying genetic defect in the lamin A gene leads to accumulation at the nuclear lamina of progerin-a mutant form of lamin A that cannot be correctly processed. This has been reported to result in defects in the DNA damage response and in DNA repair, leading to the hypothesis that, as in normal ageing and in other progeroid syndromes caused by mutation of genes of the DNA repair and DNA damage response pathways, increased DNA damage may be responsible for the premature ageing phenotypes in HGPS patients...
May 6, 2017: Chromosome Research
https://www.readbyqxmd.com/read/28423660/progerin-impairs-vascular-smooth-muscle-cell-growth-via-the-dna-damage-response-pathway
#4
Daisuke Kinoshita, Ayako Nagasawa, Ippei Shimizu, Takashi K Ito, Yohko Yoshida, Masanori Tsuchida, Atsushi Iwama, Toshiya Hayano, Tohru Minamino
Mutations of the lamin A gene cause various premature aging syndromes, including Hutchinson-Gilford progeria syndrome (HGPS) and atypical Werner syndrome. In HGPS (but not atypical Werner syndrome), extensive loss of vascular smooth muscle cells leads to myocardial infarction with premature death. The underlying mechanisms how single gene mutations can cause various phenotypes are largely unknown. We performed an interactome analysis using mutant forms of lamin A involved in progeroid syndromes. We found that the mutant lamin A responsible for HGPS, known as progerin, could not bind to proteins related to the DNA damage response, including DNA-dependent protein kinase (DNA-PK)...
May 23, 2017: Oncotarget
https://www.readbyqxmd.com/read/28420447/ck2-1-a-bone-morphogenetic-protein-receptor-type-ia-mimetic-peptide-repairs-cartilage-in-mice-with-destabilized-medial-meniscus
#5
Hemanth Akkiraju, Padma Pradeepa Srinivasan, Xian Xu, Xinqiao Jia, Catherine B Kirn Safran, Anja Nohe
BACKGROUND: Osteoarthritis (OA) of the knee involves degeneration of articular cartilage of the diarthrodial joints. Current treatment options temporarily relieve the joint pain but do not restore the lost cartilage. We recently designed a novel bone morphogenetic protein receptor type I (BMPRI) mimetic peptide, CK2.1, that activates BMPRIa signaling in the absence of bone morphogenetic protein (BMP). Our previous research demonstrated that CK2.1 induced chondrogenesis in vitro and in vivo; however, it is unknown if CK2...
April 18, 2017: Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/28317242/chemical-screening-identifies-rock-as-a-target-for-recovering-mitochondrial-function-in-hutchinson-gilford-progeria-syndrome
#6
Hyun Tae Kang, Joon Tae Park, Kobong Choi, Hyo Jei Claudia Choi, Chul Won Jung, Gyu Ree Kim, Young-Sam Lee, Sang Chul Park
Hutchinson-Gilford progeria syndrome (HGPS) constitutes a genetic disease wherein an aging phenotype manifests in childhood. Recent studies indicate that reactive oxygen species (ROS) play important roles in HGPS phenotype progression. Thus, pharmacological reduction in ROS levels has been proposed as a potentially effective treatment for patient with this disorder. In this study, we performed high-throughput screening to find compounds that could reduce ROS levels in HGPS fibroblasts and identified rho-associated protein kinase (ROCK) inhibitor (Y-27632) as an effective agent...
June 2017: Aging Cell
https://www.readbyqxmd.com/read/28314379/rejuvenation-by-partial-reprogramming-of-the-epigenome
#7
Andrew R Mendelsohn, James W Larrick, Jennifer L Lei
Epigenetic variation with age is one of the most important hallmarks of aging. Resetting or repairing the epigenome of aging cells in intact animals may rejuvenate the cells and perhaps the entire organism. In fact, differentiated adult cells, which by definition have undergone some epigenetic changes, are capable of being rejuvenated and reprogrammed to create pluripotent stem cells and viable cloned animals. Apparently, such reprogramming is capable of completely resetting the epigenome. However, attempts to fully reprogram differentiated cells in adult animals have failed in part because reprogramming leads to the formation of teratomas...
April 2017: Rejuvenation Research
https://www.readbyqxmd.com/read/28229933/nuclear-lamins-and-progerin-are-dispensable-for-antioxidant-nrf2-response-to-arsenic-and-cadmium
#8
Kazunori Hashimoto, Rima Majumdar, Yoshiaki Tsuji
Lamins are important constituents of the nuclear inner membrane and provide a platform for transcription factors and chromatin. Progerin, a C-terminal truncated lamin A mutant, causes premature aging termed Hutchinson-Gilford Progeria Syndrome (HGPS). Oxidative stress appears to be involved in the pathogenesis of HGPS, although the mechanistic role of progerin remains elusive. Here we examined whether nuclear lamins are important for a cellular antioxidant mechanism, and whether progerin compromises it. We investigated the activation of nuclear factor-E2-related factor 2 (Nrf2) which regulates various antioxidant genes including heme oxygenase-1 (HMOX1), following exposure to sodium arsenite or cadmium chloride in lamin knockdown human cell lines and primary HGPS human fibroblasts...
May 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28211642/biomechanical-strain-exacerbates-inflammation-on-a-progeria-on-a-chip-model
#9
João Ribas, Yu Shrike Zhang, Patrícia R Pitrez, Jeroen Leijten, Mario Miscuglio, Jeroen Rouwkema, Mehmet Remzi Dokmeci, Xavier Nissan, Lino Ferreira, Ali Khademhosseini
Organ-on-a-chip platforms seek to recapitulate the complex microenvironment of human organs using miniaturized microfluidic devices. Besides modeling healthy organs, these devices have been used to model diseases, yielding new insights into pathophysiology. Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disease showing accelerated vascular aging, leading to the death of patients due to cardiovascular diseases. HGPS targets primarily vascular cells, which reside in mechanically active tissues...
February 17, 2017: Small
https://www.readbyqxmd.com/read/28192606/metformin-alleviates-ageing-cellular-phenotypes-in-hutchinson-gilford-progeria-syndrome-dermal-fibroblasts
#10
Seul-Ki Park, Ok Sarah Shin
Metformin is a popular antidiabetic biguanide, which has been considered as a candidate drug for cancer treatment and ageing prevention. Hutchinson-Gilford progeria syndrome (HGPS) is a devastating disease characterized by premature ageing and severe age-associated complications leading to death. The effects of metformin on HGPS dermal fibroblasts remain largely undefined. In this study, we investigated whether metformin could exert a beneficial effect on nuclear abnormalities and delay senescence in fibroblasts derived from HGPS patients...
February 13, 2017: Experimental Dermatology
https://www.readbyqxmd.com/read/27974395/lamins-and-metabolism
#11
REVIEW
Chayki Charar, Yosef Gruenbaum
Lamins are nuclear intermediate filaments (IFs) with important roles in most nuclear activities, including nuclear organization and cell-cycle progression. Mutations in human lamins cause over 17 different diseases, termed laminopathies. Most of these diseases are autosomal dominant and can be roughly divided into four major groups: muscle diseases, peripheral neuronal diseases, accelerated aging disorders and metabolic diseases including Dunnigan type familial partial lipodystrophy (FLPD), acquired partial lipodystrophy (APL) and autosomal dominant leucodystrophy...
January 1, 2017: Clinical Science (1979-)
https://www.readbyqxmd.com/read/27929926/comparing-lamin-proteins-post-translational-relative-stability-using-a-2a-peptide-based-system-reveals-elevated-resistance-of-progerin-to-cellular-degradation
#12
COMPARATIVE STUDY
Di Wu, Phillip A Yates, Haoyue Zhang, Kan Cao
Nuclear lamins are the major components of the nuclear lamina at the periphery of the nucleus, supporting the nuclear envelope and participating in many nuclear processes, including DNA replication, transcription and chromatin organization. A group of diseases, the laminopathies, is associated with mutations in lamin genes. One of the most striking cases is Hutchinson-Gilford progeria syndrome (HGPS) which is the consequence of a lamin A dominant negative mutant named progerin. Due to the abnormal presence of a permanent C-terminal farnesyl tail, progerin gradually accumulates on the nuclear membrane, perturbing a diversity of signalings and transcriptional events...
November 2016: Nucleus
https://www.readbyqxmd.com/read/27920058/a-novel-somatic-mutation-achieves-partial-rescue-in-a-child-with-hutchinson-gilford-progeria-syndrome
#13
Daniel Z Bar, Martin F Arlt, Joan F Brazier, Wendy E Norris, Susan E Campbell, Peter Chines, Delphine Larrieu, Stephen P Jackson, Francis S Collins, Thomas W Glover, Leslie B Gordon
BACKGROUND: Hutchinson-Gilford progeria syndrome (HGPS) is a fatal sporadic autosomal dominant premature ageing disease caused by single base mutations that optimise a cryptic splice site within exon 11 of the LMNA gene. The resultant disease-causing protein, progerin, acts as a dominant negative. Disease severity relies partly on progerin levels. METHODS AND RESULTS: We report a novel form of somatic mosaicism, where a child possessed two cell populations with different HGPS disease-producing mutations of the same nucleotide-one producing severe HGPS and one mild HGPS...
March 2017: Journal of Medical Genetics
https://www.readbyqxmd.com/read/27907109/loss-of-h3k9me3-correlates-with-atm-activation-and-histone-h2ax-phosphorylation-deficiencies-in-hutchinson-gilford-progeria-syndrome
#14
Haoyue Zhang, Linlin Sun, Kun Wang, Di Wu, Mason Trappio, Celeste Witting, Kan Cao
Compelling evidence suggests that defective DNA damage response (DDR) plays a key role in the premature aging phenotypes in Hutchinson-Gilford progeria syndrome (HGPS). Studies document widespread alterations in histone modifications in HGPS cells, especially, the global loss of histone H3 trimethylated on lysine 9 (H3K9me3). In this study, we explore the potential connection(s) between H3K9me3 loss and the impaired DDR in HGPS. When cells are exposed to a DNA-damaging agent Doxorubicin (Dox), double strand breaks (DSBs) are generated that result in the phosphorylation of histone H2A variant H2AX (gammaH2AX) within an hour...
2016: PloS One
https://www.readbyqxmd.com/read/27859259/vessel-co-option-is-common-in-human-lung-metastases-and-mediates-resistance-to-anti-angiogenic-therapy-in-preclinical-lung-metastasis-models
#15
Victoria L Bridgeman, Peter B Vermeulen, Shane Foo, Agnes Bilecz, Frances Daley, Eleftherios Kostaras, Mark R Nathan, Elaine Wan, Sophia Frentzas, Thomas Schweiger, Balazs Hegedus, Konrad Hoetzenecker, Ferenc Renyi-Vamos, Elizabeth A Kuczynski, Naveen S Vasudev, James Larkin, Martin Gore, Harold F Dvorak, Sandor Paku, Robert S Kerbel, Balazs Dome, Andrew R Reynolds
Anti-angiogenic therapies have shown limited efficacy in the clinical management of metastatic disease, including lung metastases. Moreover, the mechanisms via which tumours resist anti-angiogenic therapies are poorly understood. Importantly, rather than utilizing angiogenesis, some metastases may instead incorporate pre-existing vessels from surrounding tissue (vessel co-option). As anti-angiogenic therapies were designed to target only new blood vessel growth, vessel co-option has been proposed as a mechanism that could drive resistance to anti-angiogenic therapy...
February 2017: Journal of Pathology
https://www.readbyqxmd.com/read/27799555/cardiac-electrical-defects-in-progeroid-mice-and-hutchinson-gilford-progeria-syndrome-patients-with-nuclear-lamina-alterations
#16
José Rivera-Torres, Conrado J Calvo, Anna Llach, Gabriela Guzmán-Martínez, Ricardo Caballero, Cristina González-Gómez, Luis J Jiménez-Borreguero, Juan A Guadix, Fernando G Osorio, Carlos López-Otín, Adela Herraiz-Martínez, Nuria Cabello, Alex Vallmitjana, Raul Benítez, Leslie B Gordon, José Jalife, José M Pérez-Pomares, Juan Tamargo, Eva Delpón, Leif Hove-Madsen, David Filgueiras-Rama, Vicente Andrés
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease caused by defective prelamin A processing, leading to nuclear lamina alterations, severe cardiovascular pathology, and premature death. Prelamin A alterations also occur in physiological aging. It remains unknown how defective prelamin A processing affects the cardiac rhythm. We show age-dependent cardiac repolarization abnormalities in HGPS patients that are also present in the Zmpste24(-/-) mouse model of HGPS. Challenge of Zmpste24(-/-) mice with the β-adrenergic agonist isoproterenol did not trigger ventricular arrhythmia but caused bradycardia-related premature ventricular complexes and slow-rate polymorphic ventricular rhythms during recovery...
November 15, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27739443/a-high-throughput-phenotypic-screening-reveals-compounds-that-counteract-premature-osteogenic-differentiation-of-hgps-ips-derived-mesenchymal-stem-cells
#17
Alessandra Lo Cicero, Anne-Laure Jaskowiak, Anne-Laure Egesipe, Johana Tournois, Benjamin Brinon, Patricia R Pitrez, Lino Ferreira, Annachiara de Sandre-Giovannoli, Nicolas Levy, Xavier Nissan
Hutchinson-Gilford progeria syndrome (HGPS) is a rare fatal genetic disorder that causes systemic accelerated aging in children. Thanks to the pluripotency and self-renewal properties of induced pluripotent stem cells (iPSC), HGPS iPSC-based modeling opens up the possibility of access to different relevant cell types for pharmacological approaches. In this study, 2800 small molecules were explored using high-throughput screening, looking for compounds that could potentially reduce the alkaline phosphatase activity of HGPS mesenchymal stem cells (MSCs) committed into osteogenic differentiation...
October 14, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27677907/mechanics-in-human-fibroblasts-and-progeria-lamin-a-mutation-e145k-results-in-stiffening-of-nuclei
#18
Ketaki Apte, Reimer Stick, Manfred Radmacher
The lamina is a filamentous meshwork beneath the inner nuclear membrane that confers mechanical stability to nuclei. The E145K mutation in lamin A causes Hutchinson-Gilford progeria syndrome (HGPS). It affects lamin filament assembly and induces profound changes in the nuclear architecture. Expression of wild-type and E145K lamin A in Xenopus oocytes followed by atomic force microscopy (AFM) probing of isolated oocyte nuclei has shown significant changes in the mechanical properties of the lamina. Nuclei of oocytes expressing E145K lamin A are stiffer than those expressing wild-type lamin A...
September 28, 2016: Journal of Molecular Recognition: JMR
https://www.readbyqxmd.com/read/27617860/interruption-of-progerin-lamin-a-c-binding-ameliorates-hutchinson-gilford-progeria-syndrome-phenotype
#19
Su-Jin Lee, Youn-Sang Jung, Min-Ho Yoon, So-Mi Kang, Ah-Young Oh, Jee-Hyun Lee, So-Young Jun, Tae-Gyun Woo, Ho-Young Chun, Sang Kyum Kim, Kyu Jin Chung, Ho-Young Lee, Kyeong Lee, Guanghai Jin, Min-Kyun Na, Nam Chul Ha, Clea Bárcena, José M P Freije, Carlos López-Otín, Gyu Yong Song, Bum-Joon Park
Hutchinson-Gilford progeria syndrome (HGPS) is a rare autosomal dominant genetic disease that is caused by a silent mutation of the LMNA gene encoding lamins A and C (lamin A/C). The G608G mutation generates a more accessible splicing donor site than does WT and produces an alternatively spliced product of LMNA called progerin, which is also expressed in normal aged cells. In this study, we determined that progerin binds directly to lamin A/C and induces profound nuclear aberrations. Given this observation, we performed a random screening of a chemical library and identified 3 compounds (JH1, JH4, and JH13) that efficiently block progerin-lamin A/C binding...
October 3, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27598002/the-glasgow-prognostic-score-and-its-variants-predict-mortality-in-living-donor-but-not-in-deceased-donor-liver-transplantation-for-hepatocellular-carcinoma-a-double-center-validation-study
#20
Alexander Kaltenborn, Harald Schrem, Benedikt Reichert, Felix Braun, Nikos Emmanouilidis, Jürgen Klempnauer, Thomas Becker, Nils Heits
AIM: This study aimed to evaluate whether the Glasgow Prognostic Score (GPS) and its variants are able to predict mortality in live donor and deceased donor liver transplantation for hepatocellular carcinoma. METHODS: Data of 29 live donor and 319 deceased donor transplantations from two German transplant centers was analyzed. The GPS, modified GPS, hepatic GPS, and Abe score were investigated. Receiver operating characteristic (ROC) curve analysis was carried out to calculate the sensitivity, specificity, and overall model correctness of the investigated scores as a predictive model...
September 6, 2016: Hepatology Research: the Official Journal of the Japan Society of Hepatology
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