The NSL complex maintains nuclear architecture stability via lamin A/C acetylation
| Autor: | Karoutas, A., Szymanski, W., Rausch, T., Guhathakurta, S., Rog-Zielinska, E. A., Peyronnet, R., Seyfferth, J., Chen, H. R., de Leeuw, R., Herquel, B., Kimura, Hiroshi, Mittler, G., Kohl, P., Medalia, O., Korbel, J. O., Akhtar, A. |
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| Přispěvatelé: | University of Zurich, Akhtar, Asifa |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Genome instability
Cell Nucleus/metabolism/*ultrastructure 610 Medicine & health Epigenesis Genetic Histones 1307 Cell Biology 03 medical and health sciences Histone H3 Mice Nuclear Proteins/genetics/*metabolism 0302 clinical medicine Heterochromatin 10019 Department of Biochemistry Animals Epigenetics Histones/genetics/metabolism Cells Cultured Histone Acetyltransferases 030304 developmental biology Cell Nucleus Mice Knockout 0303 health sciences Chemistry fungi Histone Acetyltransferases/genetics/*metabolism Nuclear Proteins Acetylation Cell Biology Fibroblasts Lamin Type A Cell biology Mice Inbred C57BL Lamin Type A/chemistry/genetics/*metabolism 030220 oncology & carcinogenesis Acetyltransferase Nuclear lamina 570 Life sciences biology Lamin NSL complex |
| Zdroj: | Nature Cell Biology |
| Popis: | While nuclear lamina abnormalities are hallmarks of human diseases, their interplay with epigenetic regulators and precise epigenetic landscape remain poorly understood. Here, we show that loss of the lysine acetyltransferase MOF or its associated NSL-complex members KANSL2 or KANSL3 leads to a stochastic accumulation of nuclear abnormalities with genomic instability patterns including chromothripsis. SILAC-based MOF and KANSL2 acetylomes identified lamin A/C as an acetylation target of MOF. HDAC inhibition or acetylation-mimicking lamin A derivatives rescue nuclear abnormalities observed in MOF-deficient cells. Mechanistically, loss of lamin A/C acetylation resulted in its increased solubility, defective phosphorylation dynamics and impaired nuclear mechanostability. We found that nuclear abnormalities include EZH2-dependent histone H3 Lys 27 trimethylation and loss of nascent transcription. We term this altered epigenetic landscape “heterochromatin enrichment in nuclear abnormalities” (HENA). Collectively, the NSL-complex-dependent lamin A/C acetylation provides a mechanism that maintains nuclear architecture and genome integrity. Karoutas et al. report lamin A/C as a non-histone target for the acetyltransferase MOF. They find that lamin A/C acetylation prevents nuclear envelope rupture and maintains nuclear integrity. |
| Databáze: | OpenAIRE |
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