PML2‐mediated thread‐like nuclear bodies mark late senescence in Hutchinson–Gilford progeria syndrome

Wang, Ming; Wang, Lulu; Qian, Minxian; Tang, Xiaolong; Liu, Zuojun; Lai, Yiwei; Ao, Ying; Huang, Yinghua; Meng, Yuan; Shi, Lei; Li, Peng; Cao, Xinyue; Wang, Zimei; Qin, Baoming; Liu, Baohua

doi:10.1111/acel.13147

Cited by 14 publications

(9 citation statements)

References 38 publications

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“…This study also found that prelamin A accumulated at PML NBs following DNA damage. Importantly, PML NB deregulation was also observed in a study investigating the effect of progerin expression [60]. Progerin is associated with Hutchinson Gilford Progeria Syndrome (HGPS) and, like prelamin A is a permanently farnesylated lamin A precursor, but unlike prelamin A, it has a 50 amino acid deletion [61].…”

Section: Nuclear Actin Responds To a Myriad Of Dna Damage Lesions And...mentioning

confidence: 89%

Filamentous nuclear actin regulation of PML NBs during the DNA damage response is deregulated by prelamin A

et al. 2022

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Nuclear actin participates in a continuously expanding list of core processes within eukaryotic nuclei, including the maintenance of genomic integrity. In response to DNA damage, nuclear actin polymerises into filaments that are involved in the repair of damaged DNA through incompletely defined mechanisms. We present data to show that the formation of nuclear F-actin in response to genotoxic stress acts as a scaffold for PML NBs and that these filamentous networks are essential for PML NB fission and recruitment of microbodies to DNA lesions. Further to this, we demonstrate that the accumulation of the toxic lamin A precursor prelamin A induces mislocalisation of nuclear actin to the nuclear envelope and prevents the establishment of nucleoplasmic F-actin networks in response to stress. Consequently, PML NB dynamics and recruitment to DNA lesions is ablated, resulting in impaired DNA damage repair. Inhibition of nuclear export of formin mDia2 restores nuclear F-actin formation by augmenting polymerisation of nuclear actin in response to stress and rescues PML NB localisation to sites of DNA repair, leading to reduced levels of DNA damage.

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Section: Nuclear Actin Responds To a Myriad Of Dna Damage Lesions And...mentioning

confidence: 89%

Filamentous nuclear actin regulation of PML NBs during the DNA damage response is deregulated by prelamin A

et al. 2022

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“…The SAβ-gal staining reflects the activity and level of β-D-galactosidase encoded by Glb1 25 . Thus, we thought that coupling Glb1 transcription to an mCherry signal might avoid the subjective effects of SAβ-gal staining 27 and facilitate live-imaging analyses. Interestingly, the high GAC signal in MA mice points to cardiac hypertrophy, which might be one reason for the earlier mortality of GACH mice.…”

Section: Discussionmentioning

confidence: 99%

“…Glb1 +/m and wild-type MEF cells were isolated from embryos on day 13.5 of gestation. Primary normal human fibroblasts (HuFB) were isolated from the skin tissue of a healthy female donor 27 and the written informed consent was obtained from the donor. The use of human fibroblasts was approved by the Medical Ethic Committee of Shenzhen University.…”

Section: Cell Culturementioning

confidence: 99%

A Glb1-2A-mCherry reporter monitors systemic aging and predicts lifespan in middle-aged mice

et al. 2022

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The progressive decline of physiological function and the increased risk of age-related diseases challenge healthy aging. Multiple anti-aging manipulations, such as senolytics, have proven beneficial for health; however, the biomarkers that label in vivo senescence at systemic levels are lacking, thus hindering anti-aging applications. In this study, we generate a Glb1+/m‒Glb1-2A-mCherry (GAC) reporter allele at the Glb1 gene locus, which encodes lysosomal β-galactosidase—an enzyme elevated in tissues of old mice. A linear correlation between GAC signal and chronological age is established in a cohort of middle-aged (9 to 13 months) Glb1+/m mice. The high GAC signal is closely associated with cardiac hypertrophy and a shortened lifespan. Moreover, the GAC signal is exponentially increased in pathological senescence induced by bleomycin in the lung. Senolytic dasatinib and quercetin (D + Q) reduce GAC signal in bleomycin treated mice. Thus, the Glb1-2A-mCherry reporter mice monitors systemic aging and function decline, predicts lifespan, and may facilitate the understanding of aging mechanisms and help in the development of anti-aging interventions.

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“…Primary normal human dermal fibroblasts isolated from a healthy female donor (aged 24 years) ( 42 ) and HGPS dermal fibroblasts HGADFN143 (HG143) ( 6 ) were described previously. MCF-7 (Michigan Cancer Foundation 7) cells, human embryonic kidney (HEK) 293T cells, HeLa cells, and MEFs were described previously ( 33 ).…”

Section: Methodsmentioning

confidence: 99%

Progerin modulates the IGF-1R/Akt signaling involved in aging

Jiang

Fang

et al. 2022

Sci. Adv.

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Progerin, a product of LMNA mutation, leads to multiple nuclear abnormalities in patients with Hutchinson-Gilford progeria syndrome (HGPS), a devastating premature aging disorder. Progerin also accumulates during physiological aging. Here, we demonstrate that impaired insulin-like growth factor 1 receptor (IGF-1R)/Akt signaling pathway results in severe growth retardation and premature aging in Zmpste24 −/− mice, a mouse model of progeria. Mechanistically, progerin mislocalizes outside of the nucleus, interacts with the IGF-1R, and down-regulates its expression, leading to inhibited mitochondrial respiration, retarded cell growth, and accelerated cellular senescence. Pharmacological treatment with the PTEN (phosphatase and tensin homolog deleted on chromosome 10) inhibitor bpV (HOpic) increases Akt activity and improves multiple abnormalities in Zmpste24-deficient mice. These findings provide previously unidentified insights into the role of progerin in regulating the IGF-1R/Akt signaling in HGPS and might be useful for treating LMNA -associated progeroid disorders.

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PML2‐mediated thread‐like nuclear bodies mark late senescence in Hutchinson–Gilford progeria syndrome

Cited by 14 publications

References 38 publications

Filamentous nuclear actin regulation of PML NBs during the DNA damage response is deregulated by prelamin A

Filamentous nuclear actin regulation of PML NBs during the DNA damage response is deregulated by prelamin A

A Glb1-2A-mCherry reporter monitors systemic aging and predicts lifespan in middle-aged mice

Progerin modulates the IGF-1R/Akt signaling involved in aging

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