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      Lamin A safeguards the m 6A methylase METTL14 nuclear speckle reservoir to prevent cellular senescence


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          Mutations in LMNA gene are frequently identified in patients suffering from a genetic disorder known as Hutchison–Gilford progeria syndrome (HGPS), providing an ideal model for the understanding of the mechanisms of aging. Lamin A, encoded by LMNA, is an essential component of the subnuclear domain‒nuclear speckles; however, the functional significance in aging is unclear. Here, we show that Lamin A interacts with the m 6A methyltransferases, METTL3 and METTL14 in nuclear speckles. Lamin A deficiency compromises the nuclear speckle METTL3/14 reservoir and renders these methylases susceptible to proteasome‐mediated degradation. Moreover, METTL3/14 levels progressively decline in cells undergoing replicative senescence. Overexpression of METTL14 attenuates both replicative senescence and premature senescence. The data reveal an essential role for Lamin A in safeguarding the nuclear speckle reservoir of the m 6A methylase METTL14 to antagonize cellular senescence.


          Lamin A interacts with the m 6A methylase METTL14 to ensure the proper localization in the nuclear speckles and protein stability. METTL14 declines in senescent cells, while its overexpression antagonizes cellular senescence.

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          Genomic instability in laminopathy-based premature aging.

          Premature aging syndromes often result from mutations in nuclear proteins involved in the maintenance of genomic integrity. Lamin A is a major component of the nuclear lamina and nuclear skeleton. Truncation in lamin A causes Hutchinson-Gilford progerial syndrome (HGPS), a severe form of early-onset premature aging. Lack of functional Zmpste24, a metalloproteinase responsible for the maturation of prelamin A, also results in progeroid phenotypes in mice and humans. We found that Zmpste24-deficient mouse embryonic fibroblasts (MEFs) show increased DNA damage and chromosome aberrations and are more sensitive to DNA-damaging agents. Bone marrow cells isolated from Zmpste24-/- mice show increased aneuploidy and the mice are more sensitive to DNA-damaging agents. Recruitment of p53 binding protein 1 (53BP1) and Rad51 to sites of DNA lesion is impaired in Zmpste24-/- MEFs and in HGPS fibroblasts, resulting in delayed checkpoint response and defective DNA repair. Wild-type MEFs ectopically expressing unprocessible prelamin A show similar defects in checkpoint response and DNA repair. Our results indicate that unprocessed prelamin A and truncated lamin A act dominant negatively to perturb DNA damage response and repair, resulting in genomic instability which might contribute to laminopathy-based premature aging.
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            Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome.

            Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by features reminiscent of marked premature ageing. Here, we present evidence of mutations in lamin A (LMNA) as the cause of this disorder. The HGPS gene was initially localized to chromosome 1q by observing two cases of uniparental isodisomy of 1q-the inheritance of both copies of this material from one parent-and one case with a 6-megabase paternal interstitial deletion. Sequencing of LMNA, located in this interval and previously implicated in several other heritable disorders, revealed that 18 out of 20 classical cases of HGPS harboured an identical de novo (that is, newly arisen and not inherited) single-base substitution, G608G(GGC > GGT), within exon 11. One additional case was identified with a different substitution within the same codon. Both of these mutations result in activation of a cryptic splice site within exon 11, resulting in production of a protein product that deletes 50 amino acids near the carboxy terminus. Immunofluorescence of HGPS fibroblasts with antibodies directed against lamin A revealed that many cells show visible abnormalities of the nuclear membrane. The discovery of the molecular basis of this disease may shed light on the general phenomenon of human ageing.
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              Lamin A-dependent nuclear defects in human aging.

              Mutations in the nuclear structural protein lamin A cause the premature aging syndrome Hutchinson-Gilford progeria (HGPS). Whether lamin A plays any role in normal aging is unknown. We show that the same molecular mechanism responsible for HGPS is active in healthy cells. Cell nuclei from old individuals acquire defects similar to those of HGPS patient cells, including changes in histone modifications and increased DNA damage. Age-related nuclear defects are caused by sporadic use, in healthy individuals, of the same cryptic splice site in lamin A whose constitutive activation causes HGPS. Inhibition of this splice site reverses the nuclear defects associated with aging. These observations implicate lamin A in physiological aging.

                Author and article information

                Aging Cell
                Aging Cell
                Aging Cell
                John Wiley and Sons Inc. (Hoboken )
                19 August 2020
                October 2020
                : 19
                : 10 ( doiID: 10.1111/acel.v19.10 )
                [ 1 ] Shenzhen Key Laboratory for Systemic Aging and Intervention National Engineering Research Center for Biotechnology (Shenzhen) Shenzhen University Shenzhen China
                [ 2 ] Department of Biochemistry & Molecular Biology Guangdong Key Laboratory of Genome Stability and Human Disease Prevention School of Basic Medical Sciences Shenzhen University Shenzhen China
                [ 3 ] Shenzhen University‐Friedrich Schiller Universität Jena Joint PhD Program Friedrich Schiller Universität Jena Germany
                [ 4 ] Carson International Cancer Center Shenzhen University Shenzhen China
                [ 5 ] Guangdong Provincial Key Laboratory of Regional Immunity and Diseases School of Basic Medical Sciences Shenzhen University Health Science Center Shenzhen China
                Author notes
                [*] [* ] Correspondence

                Zimei Wang and Baohua Liu, Shenzhen Key Laboratory for Systemic Aging and Intervention, National Engineering Research Center for Biotechnology (Shenzhen), Shenzhen University, Shenzhen 518055, China.

                Emails: wangzm@ 123456szu.edu.cn (ZW); ppliew@ 123456szu.edu.cn (BL)

                © 2020 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 5, Tables: 0, Pages: 9, Words: 4588
                Funded by: Science and Technology Program of Guangdong Province
                Award ID: 2017B030301016
                Award ID: 2019B030301009
                Funded by: Shenzhen Municipal Commission of Science and Technology Innovation
                Award ID: JCYJ20180507182044945
                Award ID: KQJSCX20180328093403969
                Award ID: ZDSYS20190902093401689
                Funded by: National Key R&D Program of China
                Award ID: 2017YFA0503900
                Funded by: National Natural Science Foundation of China
                Award ID: 81702909
                Award ID: 81871114
                Award ID: 81972602
                Award ID: 91849208
                Original Article
                Original Articles
                Custom metadata
                October 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.9.3 mode:remove_FC converted:21.10.2020

                Cell biology
                lamin a,mettl14,mettl3,nuclear speckle
                Cell biology
                lamin a, mettl14, mettl3, nuclear speckle


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