NSMCE2 suppresses cancer and aging in mice independently of its SUMO ligase activity

• Published in: The EMBO journal 2015-11, Vol.34 (21), p.2604-2619
• Main Authors: Jacome, Ariana, Gutierrez-Martinez, Paula, Schiavoni, Federica, Tenaglia, Enrico, Martinez, Paula, Rodríguez-Acebes, Sara, Lecona, Emilio, Murga, Matilde, Méndez, Juan, Blasco, Maria A, Fernandez-Capetillo, Oscar
• Format: Article
• Language: English
• Subjects: Aging; Animals; B-Lymphocytes - enzymology; Base Sequence; Cancer; Cells, Cultured; Chromosome Segregation; Chromosomes; Deoxyribonucleic acid; DNA; DNA Breaks, Double-Stranded; DNA Mutational Analysis; DNA Replication; EMBO13; EMBO31; Female; Haploinsufficiency; Humans; Life span; Ligases; Lymphocytes; Medicin och hälsovetenskap; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; mouse models; Mutation; Neoplasms - enzymology; NSMCE2; Protein Transport; RecQ Helicases - metabolism; SMC5/6; SUMO; Sumoylation; Tumor Suppressor Proteins - physiology; Ubiquitin-Protein Ligases - physiology; Yeasts
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.15252/embj.201591829

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. Synopsis The conserved Structural Maintenance of Chromosomes (SMC) complex SMC5/6 maintains genome stability and contains a subunit with SUMO E3 ligase activity, NSMCE2/MMS21. Characterization of mutant mice reveals that NSMCE2 limits cancer and aging, but that its SUMO ligase activity is largely dispensable in mice. NSMCE2 deficiency promotes cancer and aging in mice. NSMCE2‐deficient cells undergo normal DNA replication. Lack of NSMCE2 leads to cellular and animal phenotypes reminiscent of Bloom's Syndrome. Bloom's Syndrome helicase BLM and NSMCE2 independently suppress recombination and chromosome missegregation. Mutant NSMCE2 lacking only SUMO ligase activity has no overt effects on murine development or lifespan. Graphical Abstract The SMC5/6 complex subunit NSMCE2/MMS21 has an essential role in limiting recombination and facilitating chromosome segregation in mice, but does not require its SUMO ligase function to support normal murine development and life span.