@article{%a1.%Yb_44,

title = {The role of prelamin A post-translational maturation in stress response and 53BP1 recruitment},

author = {Capanni C and Schena E and Di Giampietro ML and Montecucco A and Mattioli E and Lattanzi G},

url = {https://www.frontiersin.org/articles/10.3389/fcell.2022.1018102/full},

doi = {10.3389/fcell.2022.1018102},

year  = {2022},

date = {2022-03-31},

journal = {Frontiers in cell and developmental biology},

volume = {10},

abstract = {Lamin A is a main constituent of the nuclear lamina and contributes to nuclear shaping, mechano-signaling transduction and gene regulation, thus affecting major cellular processes such as cell cycle progression and entry into senescence, cellular differentiation and stress response. The role of lamin A in stress response is particularly intriguing, yet not fully elucidated, and involves prelamin A post-translational processing. Here, we propose prelamin A as the tool that allows lamin A plasticity during oxidative stress response and permits timely 53BP1 recruitment to DNA damage foci. We show that while PCNA ubiquitination, p21 decrease and H2AX phosphorylation occur soon after stress induction in the absence of prelamin A, accumulation of non-farnesylated prelamin A follows and triggers recruitment of 53BP1 to lamin A/C complexes. Then, the following prelamin A processing steps causing transient accumulation of farnesylated prelamin A and maturation to lamin A reduce lamin A affinity for 53BP1 and favor its release and localization to DNA damage sites. Consistent with these observations, accumulation of prelamin A forms in cells under basal conditions impairs histone H2AX phosphorylation, PCNA ubiquitination and p21 degradation, thus affecting the early stages of stress response. As a whole, our results are consistent with a physiological function of prelamin A modulation during stress response aimed at timely recruitment/release of 53BP1 and other molecules required for DNA damage repair. In this context, it becomes more obvious how farnesylated prelamin A accumulation to toxic levels alters timing of DNA damage signaling and 53BP1 recruitment, thus contributing to cellular senescence and accelerated organismal aging as observed in progeroid laminopathies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Ybh,

title = {The wide and growing range of lamin B-related diseases: from laminopathies to cancer. },

author = {Evangelisti C and Rusciano I and Mongiorgi S and Ramazzotti G and Lattanzi G and Manzoli L and Cocco L and Ratti S and},

url = {https://link.springer.com/article/10.1007/s00018-021-04084-2},

doi = {10.1007/s00018-021-04084-2},

year  = {2022},

date = {2022-03-21},

journal = {Cellular and molecular life sciences},

volume = {79},

number = {126},

issue = {2},

abstract = {B-type lamins are fundamental components of the nuclear lamina, a complex structure that acts as a scaffold for organization and function of the nucleus. Lamin B1 and B2, the most represented isoforms, are encoded by LMNB1 and LMNB2 gene, respectively. All B-type lamins are synthesized as precursors and undergo sequential post-translational modifications to generate the mature protein. B-type lamins are involved in a wide range of nuclear functions, including DNA replication and repair, regulation of chromatin and nuclear stiffness. Moreover, lamins B1 and B2 regulate several cellular processes, such as tissue development, cell cycle, cellular proliferation, senescence, and DNA damage response. During embryogenesis, B-type lamins are essential for organogenesis, in particular for brain development. As expected from the numerous and pivotal functions of B-type lamins, mutations in their genes or fluctuations in their expression levels are critical for the onset of several diseases. Indeed, a growing range of human disorders have been linked to lamin B1 or B2, increasing the complexity of the group of diseases collectively known as laminopathies. This review highlights the recent findings on the biological role of B-type lamins under physiological or pathological conditions, with a particular emphasis on brain disorders and cancer.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Yb,

title = {Skeletal and Cardiac Muscle Disorders Caused by Mutations in Genes Encoding Intermediate Filament Proteins},

author = {Maggi L and Mavroidis M and Psarras S and Capetanaki Y and Lattanzi G},

url = {https://www.mdpi.com/1422-0067/22/8/4256},

doi = {10.3390/ijms22084256},

year  = {2021},

date = {2021-05-17},

journal = {International journal of molecular sciences},

volume = {22},

number = {8},

pages = {4256},

abstract = {Intermediate filaments are major components of the cytoskeleton. Desmin and synemin, cytoplasmic intermediate filament proteins and A-type lamins, nuclear intermediate filament proteins, play key roles in skeletal and cardiac muscle. Desmin, encoded by the DES gene (OMIM *125660) and A-type lamins by the LMNA gene (OMIM *150330), have been involved in striated muscle disorders. Diseases include desmin-related myopathy and cardiomyopathy (desminopathy), which can be manifested with dilated, restrictive, hypertrophic, arrhythmogenic, or even left ventricular non-compaction cardiomyopathy, Emery-Dreifuss Muscular Dystrophy (EDMD2 and EDMD3, due to LMNA mutations), LMNA-related congenital Muscular Dystrophy (L-CMD) and LMNA-linked dilated cardiomyopathy with conduction system defects (CMD1A). Recently, mutations in synemin (SYNM gene, OMIM *606087) have been linked to cardiomyopathy. This review will summarize clinical and molecular aspects of desmin-, lamin- and synemin-related striated muscle disorders with focus on LMNA and DES-associated clinical entities and will suggest pathogenetic hypotheses based on the interplay of desmin and lamin A/C. In healthy muscle, such interplay is responsible for the involvement of this network in mechanosignaling, nuclear positioning and mitochondrial homeostasis, while in disease it is disturbed, leading to myocyte death and activation of inflammation and the associated secretome alterations.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_90,

title = {The role of transposable elements activity in aging and their possible involvement in laminopathic diseases.},

author = {Andrenacci D and Cavaliere V and Lattanzi G},

url = {https://www.sciencedirect.com/science/article/pii/S1568163719301837?via%3Dihub},

doi = {10.1016/j.arr.2019.100995},

year  = {2020},

date = {2020-01-08},

journal = {Ageing research reviews},

volume = {57},

pages = {100995},

abstract = {Eukaryotic genomes contain a large number of transposable elements, part of which are still active and able to transpose in the host genome. Mobile element activation is repressed to avoid deleterious effects, such as gene mutations or chromosome rearrangements. Control of transposable elements includes a variety of mechanisms comprising silencing pathways, which are based on the production of small non-coding RNAs. Silencing can occur either through transposable element RNA degradation or through the targeting of DNA sequences by heterochromatin formation and consequent transcriptional inhibition. Since the important role of the heterochromatin silencing, the gradual loss of heterochromatin marks in constitutive heterochromatin regions during the aging process promotes derepression of transposable elements, which is considered a cause of the progressive increase in genomic instability and of the activation of inflammatory responses. This review provides an overview of the effects of heterochromatin loss on the activity of transposable elements during the aging process and the possible impact on genome function. In this context, we discuss the possible role of the nuclear lamina, a major player in heterochromatin dynamics, in the regulation of transposable element activity and potential implications in laminopathic diseases.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_439,

title = {Transportin 3 (TNPO3) and related proteins in limb girdle muscular dystrophy D2 muscle biopsies: A morphological study and pathogenetic hypothesis},

author = {Costa R and Rodia MT and Vianello S and Santi S and Lattanzi G and Angelini C and Pegoraro E and Cenacchi G},

url = {https://www.nmd-journal.com/article/S0960-8966(20)30122-X/pdf},

doi = {10.1016/j.nmd.2020.05.006},

year  = {2020},

date = {2020-01-01},

journal = {Neuromuscular disorders},

abstract = {LGMD D2 is a disease caused by TNPO3 mutation. We describe the expression of TNPO3 and selected proteins, likely modified by TNPO3 mutation, in muscle biopsies of affected patients. We also aim to find other genes involved in pathways correlated to TNPO3. Our morphological study on LGMD D2 muscle described the expression of TNPO3 and SRSF1, a splicing factor transported by TNPO3. Moreover, we investigated some sarcomeric and nuclear proteins, likely altered by TNPO3 mutation. Through an in silico approach we tried to identify genes involved in pathways that include, besides TNPO3 and SRSF1, p62 and Murf-1, altered in LGMD D2. In patients' muscles TNPO3 appeared weaker and randomly organized, with sporadic cytoplasmic aggregates positive for TNPO3; both SRSF1 and sarcomeric alpha actinin showed a different expression, while there were no alterations in the expression of the nuclear proteins. The in silico study lead to identify five genes, all coding for proteins responsible for muscle contraction. Our data suggest a possible interference in the morphology and function of myofibrillar network by mutated TNPO3; these findings are supported by the in silico identification of genes involved in muscle contraction that could help to explain the pathogenic mechanisms of LGMD D2.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_74,

title = {Statins and Histone Deacetylase Inhibitors Affect Lamin A/C - Histone Deacetylase 2 Interaction in Human Cells.},

author = {Mattioli E and Andrenacci D and Mai A and Valente S and Robijns J and De Vos WH and Capanni C and Lattanzi G},

url = {https://www.frontiersin.org/articles/10.3389/fcell.2019.00006/full},

doi = {10.3389/fcell.2019.00006},

year  = {2019},

date = {2019-03-08},

urldate = {2019-03-08},

journal = {Frontiers in cell and developmental biology},

volume = {7},

pages = {6},

abstract = {We recently identified lamin A/C as a docking molecule for human histone deacetylase 2 (HDAC2) and showed involvement of HDAC2-lamin A/C complexes in the DNA damage response. We further showed that lamin A/C-HDAC2 interaction is altered in Hutchinson-Gilford Progeria syndrome and other progeroid laminopathies. Here, we show that both inhibitors of lamin A maturation and small molecules inhibiting HDAC activity affect lamin A/C interaction with HDAC2. While statins, which inhibit prelamin A processing, reduce protein interaction, HDAC inhibitors strengthen protein binding. Moreover, treatment with HDAC inhibitors restored the enfeebled lamin A/C-HDAC2 interaction observed in HGPS cells. Based on these results, we propose that prelamin A levels as well as HDAC2 activation status might influence the extent of HDAC2 recruitment to the lamin A/C-containing platform and contribute to modulate HDAC2 activity. Our study links prelamin A processing to HDAC2 regulation and provides new insights into the effect of statins and histone deacetylase inhibitors on lamin A/C functionality in normal and progeroid cells.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y%t,

title = {The Cutting Edge: The Role of mTOR Signaling in Laminopathies.},

author = {Chiarini F and Evangelisti C and Cenni V and Fazio A and Paganelli F and Martelli AM and Lattanzi G},

doi = {10.3390/ijms20040847},

year  = {2019},

date = {2019-02-06},

journal = {International journal of molecular sciences},

volume = {20},

number = {4},

pages = {E847},

abstract = {The mechanistic target of rapamycin (mTOR) is a ubiquitous serine/threonine kinase that regulates anabolic and catabolic processes, in response to environmental inputs. The existence of mTOR in numerous cell compartments explains its specific ability to sense stress, execute growth signals, and regulate autophagy. mTOR signaling deregulation is closely related to aging and age-related disorders, among which progeroid laminopathies represent genetically characterized clinical entities with well-defined phenotypes. These diseases are caused by LMNA mutations and feature altered bone turnover, metabolic dysregulation, and mild to severe segmental progeria. Different LMNA mutations cause muscular, adipose tissue and nerve pathologies in the absence of major systemic involvement. This review explores recent advances on mTOR involvement in progeroid and tissue-specific laminopathies. Indeed, hyper-activation of protein kinase B (AKT)/mTOR signaling has been demonstrated in muscular laminopathies, and rescue of mTOR-regulated pathways increases lifespan in animal models of Emery-Dreifuss muscular dystrophy. Further, rapamycin, the best known mTOR inhibitor, has been used to elicit autophagy and degradation of mutated lamin A or progerin in progeroid cells. This review focuses on mTOR-dependent pathogenetic events identified in Emery-Dreifuss muscular dystrophy, LMNA-related cardiomyopathies, Hutchinson-Gilford Progeria, mandibuloacral dysplasia, and type 2 familial partial lipodystrophy. Pharmacological application of mTOR inhibitors in view of therapeutic strategies is also discussed.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_256,

title = {The telomeric protein AKTIP interacts with A- and B-type lamins and is involved in regulation of cellular senescence.},

author = {Burla R and Carcuro M and Torre ML and Fratini F and Crescenzi M and D'Apice MR and Spitalieri P and Raffa GD and Astrologo L and Lattanzi G and Cundari E and Raimondo D and Biroccio A and Gatti M and Saggio I},

url = {http://rsob.royalsocietypublishing.org/content/6/8/160103.long},

doi = {10.1098/rsob.160103},

year  = {2016},

date = {2016-08-12},

journal = {Open Biology},

volume = {6},

number = {8},

pages = {160103},

abstract = {AKTIP is a shelterin-interacting protein required for replication of telomeric DNA. Here, we show that AKTIP biochemically interacts with A- and B-type lamins and affects lamin A, but not lamin C or B, expression. In interphase cells, AKTIP localizes at the nuclear rim and in discrete regions of the nucleoplasm just like lamins. Double immunostaining revealed that AKTIP partially co-localizes with lamin B1 and lamin A/C in interphase cells, and that proper AKTIP localization requires functional lamin A. In mitotic cells, AKTIP is enriched at the spindle poles and at the midbody of late telophase cells similar to lamin B1. AKTIP-depleted cells show senescence-associated markers and recapitulate several aspects of the progeroid phenotype. Collectively, our results indicate that AKTIP is a new player in lamin-related processes, including those that govern nuclear architecture, telomere homeostasis and cellular senescence.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_406,

title = {Slug transcription factor and nuclear Lamin B1 are upregulated in osteoarthritic chondrocytes.},

author = {Piva R and Lambertini E and Manferdini C and Capanni C and Penolazzi L and Gabusi E and Paolella F and Lolli A and Angelozzi M and Lattanzi G and Lisignoli G},

url = {https://www.sciencedirect.com/science/article/pii/S1063458415008560?via%3Dihub},

doi = {10.1016/j.joca.2015.03.015},

year  = {2015},

date = {2015-01-01},

urldate = {2015-01-01},

journal = {Osteoarthritis and Cartilage},

volume = {23},

number = {7},

pages = {1226-1230},

abstract = {OBJECTIVE: To contribute to clarify molecular mechanisms supporting senescence and de-differentiation of chondrocytes in chondrocyte pathologies such as osteoarthritis (OA). Specifically, we investigated the relationship between the nuclear lamina protein Lamin B1 and the negative regulator of chondrogenesis Slug transcription factor in osteoarthritic chondrocytes. METHODS: Lamin B1 and Slug proteins were analyzed in cartilage explants from normal subjects and OA patients by immunohistochemical technique. Their expression was confirmed on isolated chondrocytes both at passage 0 and passage 2 (de-differentiated chondrocytes) by immunofluorescence and western blot. Subsequently, we explored the "in vivo" binding of Slug on LMNB1 promoter by chromatin immunoprecipitation assay (ChIP). RESULTS: In this study we demonstrated that nuclear lamina protein Lamin B1 and anti-chondrogenic Slug transcription factor are upregulated in cartilage and OA chondrocytes. Furthermore, we found that Slug is "in vivo" recruited by LMNB1 gene promoter mostly when chondrocytes undergo de-differentiation or OA degeneration. CONCLUSIONS: We described for the first time a potential regulatory role of Slug on the LMNB1 gene expression in OA chondrocytes. These findings may have important implications for the study of premature senescence, and degeneration of cartilage, and may contribute to develop effective therapeutic strategies against signals supporting cartilage damage in different subsets of patients. Copyright 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}