title: NSMCE2 suppresses cancer and aging in mice independently of its SUMO ligase activity.
abstract: The SMC5/6 complex is the least understood of SMC complexes. In yeast, smc5/6 mutants phenocopy mutations in sgs1, the BLM ortholog that is deficient in Bloom's syndrome (BS). We here show that NSMCE2 (Mms21, in Saccharomyces cerevisiae), an essential SUMO ligase of the SMC5/6 complex, suppresses cancer and aging in mice. Surprisingly, a mutation that compromises NSMCE2-dependent SUMOylation does not have a detectable impact on murine lifespan. In contrast, NSMCE2 deletion in adult mice leads to pathologies resembling those found in patients of BS. Moreover, and whereas NSMCE2 deletion does not have a detectable impact on DNA replication, NSMCE2-deficient cells also present the cellular hallmarks of BS such as increased recombination rates and an accumulation of micronuclei. Despite the similarities, NSMCE2 and BLM foci do not colocalize and concomitant deletion of Blm and Nsmce2 in B lymphocytes further increases recombination rates and is synthetic lethal due to severe chromosome mis-segregation. Our work reveals that SUMO- and BLM-independent activities of NSMCE2 limit recombination and facilitate segregation; functions of the SMC5/6 complex that are necessary to prevent cancer and aging in mice.
authors.affiliation: Genomic Instability Group, Spanish National Cancer Research Centre, Madrid, Spain.
authors.forename: Ariana
authors.initials: A
authors.lastname: Jacome
authors.affiliation: Genomic Instability Group, Spanish National Cancer Research Centre, Madrid, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Gutierrez-Martinez
authors.affiliation: Genomic Instability Group, Spanish National Cancer Research Centre, Madrid, Spain.
authors.forename: Federica
authors.initials: F
authors.lastname: Schiavoni
authors.affiliation: Genomic Instability Group, Spanish National Cancer Research Centre, Madrid, Spain.
authors.forename: Enrico
authors.initials: E
authors.lastname: Tenaglia
authors.affiliation: Telomeres and Telomerase Group, Spanish National Cancer Research Centre, Madrid, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Martinez
authors.affiliation: DNA Replication Group, Spanish National Cancer Research Centre, Madrid, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Rodríguez-Acebes
authors.affiliation: Genomic Instability Group, Spanish National Cancer Research Centre, Madrid, Spain.
authors.forename: Emilio
authors.initials: E
authors.lastname: Lecona
authors.affiliation: Genomic Instability Group, Spanish National Cancer Research Centre, Madrid, Spain.
authors.forename: Matilde
authors.initials: M
authors.lastname: Murga
authors.affiliation: DNA Replication Group, Spanish National Cancer Research Centre, Madrid, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Méndez
authors.affiliation: Telomeres and Telomerase Group, Spanish National Cancer Research Centre, Madrid, Spain.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Blasco
authors.affiliation: Genomic Instability Group, Spanish National Cancer Research Centre, Madrid, Spain Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden ofernandez@cnio.es.
authors.forename: Oscar
authors.initials: O
authors.lastname: Fernandez-Capetillo
mesh_terms: D000375:Aging; D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology; D001483:Base Sequence; D002478:Cells, Cultured; D020090:Chromosome Segregation; D053903:DNA Breaks, Double-Stranded; D004252:DNA Mutational Analysis; D004261:DNA Replication; D005260:Female; D057895:Haploinsufficiency; D006801:Humans; D008025:Ligases; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000201:enzymology*; D021381:Protein Transport; D053484:RecQ Helicases / Q000378:metabolism; D058207:Sumoylation; D025521:Tumor Suppressor Proteins / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
chemical_list: D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; C097151:Bloom syndrome protein; D053484:RecQ Helicases; D008025:Ligases; C000605050:NSMCE2 protein, mouse
keywords: NSMCE2; SMC5/6; SUMO; chromosome segregation; mouse models