Biology subjects

En, A.

Publications and source records attributed to En, A..

3 recordsLinked to original sources

bioRxiv2026

RNA polymerase loss by nuclear rupture drives LMNA cardiomyopathy

Localized rupture of the nuclear envelope has recently been reported in various pathologies, including cancer 1,2, neurodegenerative disease 3-5, myocardial infarction 6, as well as dilated cardiomyopathy caused by Lamin A/C gene mutations (LMNA-DCM) 7. Whether and how nuclear rupture contributes to disease remains unknown. Here, we report that nuclear rupture causes global transcriptional deficiency in a mouse model of LMNA-DCM. We observed that ruptured nuclei lost RNA polymerase II, leading to downregulation of numerous genes essential for cardiomyocyte structure and function. We identified endogenous resealing of nuclear rupture as a cardioprotective mechanism in LMNA-DCM mouse hearts. Resealing involved the ESCRT-III membrane remodeling complex recruited to nuclear rupture sites. Resealed nuclei restored transcription while inhibiting ESCRT-III activity accelerated cardiomyopathy. However, resealed nuclei were short-lived: they re-ruptured at twice the rate of resealing. A kinetic model predicted progressive accumulation of ruptured nuclei despite ongoing resealing. Consistently, a human LMNA-DCM heart contained numerous ruptured nuclei at disease presentation. These findings linked nuclear rupture to organ deterioration through global transcriptional deficiency and suggested rupture resealing as a critical modifier of nuclear rupture-associated conditions.

molecular biology↗

bioRxiv2025

Disturbed proteostasis is the key event that triggers cellular senescence through the regulation of chromatin organization and genome stability

Mammalian cells undergo irreversible proliferation arrest when exposed to stresses, a phenomenon termed cellular senescence. Various types of stress induce cellular senescence; nonetheless, senescent cells show similar phenotypes overall. Thus, cells undergo cellular senescence through the similar mechanisms, regardless of the type of stress encountered. Here we aimed to reveal the mechanisms underlying cellular senescence. We have previously shown that lamin b receptor (LBR), which is a protein that regulates heterochromatin organization, was downregulated in senescent cells, and downregulation of LBR induced cellular senescence. Additionally, we have shown that downregulation of protein synthesis effectively suppressed cellular senescence. Thereby, chromatin organization and protein synthesis are implicated in the regulation of cellular senescence. We examined the roles of them in cellular senescence and found that protein synthesis was upregulated during the induction of cellular senescence, and upregulated protein synthesis caused disturbed proteostasis that led to the decreased function of LBR. Furthermore, we showed that decreased LBR function induced cellular senescence through altered chromatin organization and increased genome instability. Importantly, these findings revealed a link between protein synthesis and chromatin organization and accounted for the phenotypes of senescent cells which show disturbed proteostasis, altered chromatin organization, and increased genome instability. Our findings provided the general model for the mechanisms of cellular senescence.

cell biology↗

bioRxiv2023

The cGAS-STING pathway is dispensable in a mouse model of LMNA-cardiomyopathy despite nuclear envelope rupture

Nuclear envelope (NE) ruptures are emerging observations in Lamin-related dilated cardiomyopathy, an adult-onset disease caused by loss-of-function mutations in Lamin A/C, a nuclear lamina component. Here, we tested a prevailing hypothesis that NE ruptures trigger pathological cGAS-STING cytosolic DNA-sensing pathway, using a mouse model of Lamin-cardiomyopathy. Reduction of Lamin A/C in cardiomyocytes of adult mice caused pervasive NE ruptures in cardiomyocytes, preceding inflammatory transcription, fibrosis, and fatal dilated cardiomyopathy. NE ruptures were followed by DNA damage accumulation without causing immediate cardiomyocyte death. However, cGAS-STING-dependent inflammatory signaling remained inactive. Deleting cGas or Sting did not rescue cardiomyopathy. The lack of cGAS-STING activation was likely due to the near absence of cGAS expression in adult cardiomyocytes at baseline. Instead, extracellular matrix (ECM) signaling was activated and predicted to initiate pro-inflammatory communication from Lamin-reduced cardiomyocytes to fibroblasts. Our work nominates ECM signaling, not cGAS-STING, as a potential inflammatory contributor in Lamin-cardiomyopathy.

molecular biology↗