Off-pore Nup98 condensates mobilize heterochromatic breaks and exclude Rad51
Language English Country United States Media print-electronic
Document type Journal Article
PubMed
40480227
DOI
10.1016/j.molcel.2025.05.012
PII: S1097-2765(25)00446-0
Knihovny.cz E-resources
- Keywords
- Nup88, Nup98 condensates, Sec13, double-strand break repair, droplets, heterochromatin repair, homologous recombination, nuclear dynamics, nucleoplasmic nucleoporins, phase separation,
- MeSH
- Chromosomal Proteins, Non-Histone metabolism genetics MeSH
- Drosophila melanogaster * genetics metabolism MeSH
- DNA Breaks, Double-Stranded MeSH
- Heterochromatin * genetics metabolism MeSH
- Chromobox Protein Homolog 5 MeSH
- Nuclear Pore Complex Proteins * metabolism genetics MeSH
- Cell Cycle Proteins metabolism genetics MeSH
- Drosophila Proteins * metabolism genetics MeSH
- Recombinational DNA Repair * MeSH
- Rad51 Recombinase * metabolism genetics MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Chromosomal Proteins, Non-Histone MeSH
- Heterochromatin * MeSH
- Chromobox Protein Homolog 5 MeSH
- Nuclear Pore Complex Proteins * MeSH
- nuclear pore complex protein 98 MeSH Browser
- Cell Cycle Proteins MeSH
- Drosophila Proteins * MeSH
- Rad51 Recombinase * MeSH
Phase separation forms membraneless compartments, including heterochromatin "domains" and repair foci. Pericentromeric heterochromatin mostly comprises repeated sequences prone to aberrant recombination. In Drosophila cells, "safe" homologous recombination (HR) repair of these sequences requires their relocalization to the nuclear periphery before Rad51 recruitment and strand invasion. How this mobilization initiates is unknown, and the contribution of phase separation is unclear. Here, we show that Nup98 nucleoporin is recruited to repair sites before relocalization by Sec13 or Nup88, and downstream of the Smc5/6 complex and heterochromatin protein 1 (HP1). Remarkably, Nup98 condensates are immiscible with HP1 condensates, and they are required and sufficient to mobilize repair sites and exclude Rad51, thus preventing aberrant recombination while promoting HR repair. Disrupting this pathway results in heterochromatin repair defects and widespread chromosome rearrangements, revealing an "off-pore" role for nucleoporins and phase separation in nuclear dynamics and genome integrity in a multicellular eukaryote.
Department of Biology Faculty of Medicine Masaryk University Kamenice 5 A7 Brno 62500 Czech Republic
Department of Biology San Diego State University San Diego CA 92182 USA
Department of Chemistry University of Pennsylvania Philadelphia PA 19104 USA
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