Crucial role of the NSE1 RING domain in Smc5/6 stability and FANCM-independent fork progression

Lorite, Neus P and Apostolova, Sonia and Guasch-Vallés, Marta and Pryer, Aaron and Unzueta, Fernando and Freire, Raimundo and Solé-Soler, Roger and Pedraza, Neus and Dolcet, Xavier and Garí, Eloi and Agell, Neus and Taylor, Elaine M and Colomina, Neus and Torres-Rosell, Jordi (2024) Crucial role of the NSE1 RING domain in Smc5/6 stability and FANCM-independent fork progression. Cellular and Molecular Life Sciences : CMLS, 81 (1): 251. ISSN 1420-682X

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The Smc5/6 complex is a highly conserved molecular machine involved in the maintenance of genome integrity. While its functions largely depend on restraining the fork remodeling activity of Mph1 in yeast, the presence of an analogous Smc5/6-FANCM regulation in humans remains unknown. We generated human cell lines harboring mutations in the NSE1 subunit of the Smc5/6 complex. Point mutations or truncations in the RING domain of NSE1 result in drastically reduced Smc5/6 protein levels, with differential contribution of the two zinc-coordinating centers in the RING. In addition, nse1-RING mutant cells display cell growth defects, reduced replication fork rates, and increased genomic instability. Notably, our findings uncover a synthetic sick interaction between Smc5/6 and FANCM and show that Smc5/6 controls fork progression and chromosome disjunction in a FANCM-independent manner. Overall, our study demonstrates that the NSE1 RING domain plays vital roles in Smc5/6 complex stability and fork progression through pathways that are not evolutionary conserved.

Item Type:
Journal Article
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Cellular and Molecular Life Sciences : CMLS
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Research Output Funding/yes_externally_funded
?? 6dna replicationyes - externally fundedcellular and molecular neurosciencecell biologymolecular medicinemolecular biologypharmacology ??
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Deposited On:
10 Jun 2024 09:35
Last Modified:
11 Jun 2024 02:15