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

EMBO J. 2015 Nov 3;34(21):2604-19. doi: 10.15252/embj.201591829. Epub 2015 Oct 6.


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.

Keywords: NSMCE2; SMC5/6; SUMO; chromosome segregation; mouse models.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging*
  • Animals
  • B-Lymphocytes / enzymology
  • Base Sequence
  • Cells, Cultured
  • Chromosome Segregation
  • DNA Breaks, Double-Stranded
  • DNA Mutational Analysis
  • DNA Replication
  • Female
  • Haploinsufficiency
  • Humans
  • Ligases
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasms / enzymology*
  • Protein Transport
  • RecQ Helicases / metabolism
  • Sumoylation
  • Tumor Suppressor Proteins / physiology
  • Ubiquitin-Protein Ligases / physiology*


  • Tumor Suppressor Proteins
  • Ubiquitin-Protein Ligases
  • Bloom syndrome protein
  • RecQ Helicases
  • Ligases
  • NSMCE2 protein, mouse