NSMCE 2 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.

SMC5/6 is required for the formation of segregation-competent bivalent chromosomes during meiosis I in mouse oocytes

“…When the heterozygous Smc5 del oocytes were fertilized with sperm from the Smc5 flox/del, Hspa2-Cre males, the level of blastocysts obtained reduced by approximately half, which supports the fact that early stages of embryonic development are affected in embryos homozygous for mutation of Smc5. Homozygous mutation of other components of the SMC5/6 complex, Smc6 and Nsmce2, have also been shown to cause embryonic lethality (Jacome et al, 2015;Ju et al, 2013). Taken together with the IVF and MII data obtained for the 'juvenile' Smc5 cKO females (Figs 3 and 4, Table 2; Fig.…”

“…Therefore, it is possible that a heterozygous mutation of a SMC5/6 component could lead to age-related errors during oogenesis too. Supporting this notion, it has been shown that heterozygous mutation of Nscme2 results in increased incidences of micronuclei and polynucleation in MEFs (Jacome et al, 2015).…”

Conditional mutation of Smc5 in mouse embryonic stem cells perturbs condensin localization and mitotic progression

“…Recently, hypomorphic mutations of a Smc5/6 component, NSMCE2, have been reported to cause primordial dwarfism and microcephaly in human (Payne et al, 2014). Furthermore, SMC mutations are associated with cancer (Leiserson et al, 2015;Jacome et al, 2015). Cohesin mutations have been identified in myeloid leukemias (Leeke et al, 2014).…”

The (elusive) role of the SMC5/6 complex

“…Second, NSMCE2 fails to form ionizing radiation (IR)-induced foci in mitotic cells neither it localizes to meiotic DSBs during meiosis. 2 Third, repair of meiotic DSB in yeast or IR-induced DSBs in mammalian cells are largely unaffected by SMC5/6 deficiencies. Finally, all members of the complex are essential in yeast, but HR is not.…”

“…2 Moreover, NSMCE2 hypomorphism in humans also leads to a genomic instability syndrome that limits lifespan. 7 Hence, understanding the function of the SMC5/6 complex is still an important task, which beyond its academic interest might yield unanticipated insights with potential applications to human health.…”