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Off-pore Nup98 condensates mobilize heterochromatic breaks and exclude Rad51

C. Merigliano, T. Ryu, J. Cibulka, CC. Rawal, CD. See, A. Mitra, TW. Reynolds, NL. Butova, CP. Caridi, X. Li, J. Wang, C. Deng, DM. Chenoweth, P. Sung, M. Capelson, L. Krejčí, I. Chiolo

. 2025 ; 85 (12) : 2355-2373.e11. [pub] 20250605

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc25015286

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.

Citace poskytuje Crossref.org

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$a Phase separation forms membraneless compartments, including heterochromatin "domains" and repair foci. Pericentromeric heterochromatin mostly comprises repeated sequences prone to aberrant recombination. In Drosophila cells, "safe" homologous recombination (HR) repair of these sequences requires their relocalization to the nuclear periphery before Rad51 recruitment and strand invasion. How this mobilization initiates is unknown, and the contribution of phase separation is unclear. Here, we show that Nup98 nucleoporin is recruited to repair sites before relocalization by Sec13 or Nup88, and downstream of the Smc5/6 complex and heterochromatin protein 1 (HP1). Remarkably, Nup98 condensates are immiscible with HP1 condensates, and they are required and sufficient to mobilize repair sites and exclude Rad51, thus preventing aberrant recombination while promoting HR repair. Disrupting this pathway results in heterochromatin repair defects and widespread chromosome rearrangements, revealing an "off-pore" role for nucleoporins and phase separation in nuclear dynamics and genome integrity in a multicellular eukaryote.
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$a Ryu, Taehyun $u Department of Biological Sciences, Molecular and Computational Biology Section, University of Southern California, Los Angeles, CA 90089, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
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$a Cibulka, Jakub $u Department of Biology, Faculty of Medicine, Masaryk University, Kamenice 5/A7, Brno 62500, Czech Republic
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$a Rawal, Chetan C $u Department of Biological Sciences, Molecular and Computational Biology Section, University of Southern California, Los Angeles, CA 90089, USA
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$a Wang, Jeff $u Department of Biochemistry and Structural Biology and Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
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$a Krejčí, Lumír $u Department of Biology, Faculty of Medicine, Masaryk University, Kamenice 5/A7, Brno 62500, Czech Republic; National Centre for Biomolecular Research, Faculty of Science, Masaryk University, Kamenice 5/A4, 62500 Brno, Czech Republic
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$a Chiolo, Irene $u Department of Biological Sciences, Molecular and Computational Biology Section, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: chiolo@usc.edu
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