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Off-pore Nup98 condensates mobilize heterochromatic breaks and exclude Rad51
Chiara Merigliano1, Taehyun Ryu2, Jakub Cibulka3
1Department of Biological Sciences, Molecular and Computational Biology Section, University of Southern California, Los Angeles, CA 90089, USA.
Molecular Cell
|June 6, 2025
Summary
Nuclear pore protein Nup98 forms distinct compartments that relocate DNA repair sites. This prevents harmful recombination in heterochromatin, ensuring genome integrity.
Area of Science:
- Cell Biology
- Molecular Biology
- Genetics
Background:
- Membraneless compartments, formed by phase separation, are crucial for cellular functions like DNA repair.
- Pericentromeric heterochromatin, rich in repetitive sequences, is susceptible to aberrant recombination.
- Homologous recombination (HR) repair in Drosophila heterochromatin requires relocation to the nuclear periphery before DNA repair factor recruitment.
Purpose of the Study:
- To investigate the mechanism of DNA repair site mobilization in Drosophila heterochromatin.
- To elucidate the role of phase separation and nucleoporins in regulating homologous recombination repair.
- To understand how genome integrity is maintained at repetitive DNA sequences.
Main Methods:
- Recruitment analysis of nucleoporins (Nup98, Sec13, Nup88) at DNA repair sites.
- Investigating the spatial relationship between Nup98 and Heterochromatin Protein 1 (HP1) condensates.
- Assessing the functional requirement of Nup98 condensates for DNA repair site mobilization and Rad51 exclusion.
- Analyzing the impact of pathway disruption on heterochromatin repair and chromosome stability.
Main Results:
- Nup98 is recruited to DNA repair sites upstream of Sec13/Nup88 and downstream of Smc5/6/HP1.
- Nup98 condensates are immiscible with HP1 condensates.
- Nup98 condensates are essential and sufficient for mobilizing repair sites and excluding Rad51.
- Disruption of this pathway leads to heterochromatin repair defects and chromosome rearrangements.
Conclusions:
- Nup98-mediated phase separation drives the mobilization of DNA repair sites away from Heterochromatin Protein 1.
- This process prevents aberrant recombination by excluding Rad51, thereby promoting accurate homologous recombination repair.
- Nucleoporins play a critical role in nuclear organization and genome stability through "off-pore" phase separation mechanisms.
Keywords:
Nup88Nup98 condensatesSec13double-strand break repairdropletsheterochromatin repairhomologous recombinationnuclear dynamicsnucleoplasmic nucleoporinsphase separationMore Related Videos
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