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A high-content screen reveals new regulators of nuclear membrane stability.
Gunn, Amanda L; Yashchenko, Artem I; Dubrulle, Julien; Johnson, Jodiene; Hatch, Emily M.
Afiliación
  • Gunn AL; Divisions of Basic Sciences and Human Biology, The Fred Hutchinson Cancer Center, 1100 Fairview Ave, Seattle, Washington 98109, USA.
  • Yashchenko AI; Divisions of Basic Sciences and Human Biology, The Fred Hutchinson Cancer Center, 1100 Fairview Ave, Seattle, Washington 98109, USA.
  • Dubrulle J; Cellular Imaging Shared Resource, The Fred Hutchinson Cancer Center, 1100 Fairview Ave, Seattle, Washington 98109, USA.
  • Johnson J; Divisions of Basic Sciences and Human Biology, The Fred Hutchinson Cancer Center, 1100 Fairview Ave, Seattle, Washington 98109, USA.
  • Hatch EM; Divisions of Basic Sciences and Human Biology, The Fred Hutchinson Cancer Center, 1100 Fairview Ave, Seattle, Washington 98109, USA.
bioRxiv ; 2023 Sep 10.
Article en En | MEDLINE | ID: mdl-37398267
ABSTRACT
Nuclear membrane rupture is a physiological response to multiple in vivo processes, such as cell migration, that can cause extensive genome instability and upregulate invasive and inflammatory pathways. However, the underlying molecular mechanisms of rupture are unclear and few regulators have been identified. In this study, we developed a reporter that is size excluded from re-compartmentalization following nuclear rupture events. This allows for robust detection of factors influencing nuclear integrity in fixed cells. We combined this with an automated image analysis pipeline in a high-content siRNA screen to identify new proteins that both increase and decrease nuclear rupture frequency in cancer cells. Pathway analysis identified an enrichment of nuclear membrane and ER factors in our hits and we demonstrate that one of these, the protein phosphatase CTDNEP1, is required for nuclear stability. Further analysis of known rupture contributors, including a newly developed automated quantitative analysis of nuclear lamina gaps, strongly suggests that CTDNEP1 acts in a new pathway. Our findings provide new insights into the molecular mechanism of nuclear rupture and define a highly adaptable program for rupture analysis that removes a substantial barrier to new discoveries in the field.

Texto completo: 1 Bases de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: BioRxiv Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Bases de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: BioRxiv Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos