Article

Novel Essential DNA Repair Proteins Nse1 and Nse2 Are Subunits of the Fission Yeast Smc5-Smc6 Complex

Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 11/2003; 278(46):45460-7. DOI: 10.1074/jbc.M308828200
Source: PubMed

ABSTRACT

The structural maintenance of chromosomes (SMC) family of proteins play essential roles in genomic stability. SMC heterodimers
are required for sister-chromatid cohesion (Cohesin: Smc1 & Smc3), chromatin condensation (Condensin: Smc2 & Smc4), and DNA
repair (Smc5 & Smc6). The SMC heterodimers do not function alone and must associate with essential non-SMC subunits. To gain
further insight into the essential and DNA repair roles of the Smc5–6 complex, we have purified fission yeast Smc5 and identified
by mass spectrometry the co-precipitating proteins, Nse1 and Nse2. We show that both Nse1 and Nse2 interact with Smc5 in vivo, as part of the Smc5–6 complex. Nse1 and Nse2 are essential proteins and conserved from yeast to man. Loss of Nse1 and Nse2
function leads to strikingly similar terminal phenotypes to those observed for Smc5–6 inactivation. In addition, cells expressing
hypomorphic alleles of Nse1 and Nse2 are, like Smc5–6 mutants, hypersensitive to DNA damage. Epistasis analysis suggests that
like Smc5–6, Nse1, and Nse2 function together with Rhp51 in the homologous recombination repair of DNA double strand breaks.
The results of this study strongly suggest that Nse1 and Nse2 are novel non-SMC subunits of the fission yeast Smc5–6 DNA repair
complex.

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    • "Human orthologs were subsequently identified and were shown to be particularly abundant during meiosis (Fousteri & Lehmann, 2000). The complex contains six additional polypeptides named non-SMC elements (NSMCE) 1–6 (McDonald et al, 2003; Pebernard et al, 2004; Sergeant et al, 2005), although only four (NSMCE1-4) have been identified in mammals (Taylor et al, 2008). Besides the ATPase activity of SMC5 and SMC6, 2 additional activities are found in the complex. "
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    • "Human orthologues were subsequently identified, and shown to be particularly abundant during meiosis (Fousteri & Lehmann, 2000). The complex contains six additional polypeptides named Non SMC Elements (NSMCE) 1 to 6 (McDonald et al, 2003; Pebernard et al, 2004; Sergeant et al, 2005), although only four (NSMCE1-4) have been identified in mammals (Taylor et al, 2008). Besides the ATPase activity of SMC5 and SMC6, 2 additional activities are found in the complex. "
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    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.
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