{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNSMCE2, also known as MMS21 or NSE2, is an E3 SUMO ligase that functions as an integral subunit of the SMC5/6 complex, a critical regulator of chromatin structure and genomic stability. By mediating the conjugation of SUMO to target proteins—including SMC6, cohesin subunits such as Scc1, and additional repair factors like TRAX—NSMCE2 promotes homologous recombination repair and prevents DNA damage‐induced apoptosis. Loss of its SUMO‐ligase activity leads to hyperactivation of checkpoint kinases and a diminished capacity to repair lesions, underscoring its central role in the cellular response to DNA damage."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic and functional studies further demonstrate that impaired NSMCE2 function disrupts genome homeostasis. Compound heterozygous frameshift mutations in NSMCE2 have been linked to developmental abnormalities—including primordial dwarfism, extreme insulin resistance, and gonadal failure—accompanied by replication stress phenotypes such as increased micronucleus formation, delayed recovery of DNA synthesis, and defective recruitment of repair factors following replication fork stalling. In some leukemic cases, aberrant chimeric fusion events involving NSMCE2 and long noncoding RNAs have been identified, suggesting that misregulation of its normal function may contribute to oncogenesis. Additionally, experimental ablation of NSMCE2 leads to premature sister chromatid separation and aberrant mitotic progression, highlighting its essential role in maintaining proper chromosome cohesion."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role in DNA repair and replication recovery, NSMCE2 is pivotal during mitosis. It contributes to the resolution of topoisomerase IIα (TOP2A)‐mediated double-strand break repair intermediates by directly interacting with TOP2A. NSMCE2 catalyzes the SUMOylation of TOP2A at a novel, non‐canonical lysine residue, a modification that is required for accurate chromosome segregation. Moreover, NSMCE2 facilitates the appropriate rescue of collapsed replication forks—by promoting the timely recruitment of helicases such as BLM and preventing the persistence of repair intermediates marked by excessive RAD51 accumulation—thereby ensuring faithful sister chromatid segregation and overall genome integrity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Patrick Ryan Potts, Hongtao Yu "}, {"type": "b", "children": [{"type": "t", "text": "Human MMS21/NSE2 is a SUMO ligase required for DNA repair."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.25.16.7021-7032.2005"}], "href": "https://doi.org/10.1128/MCB.25.16.7021-7032.2005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16055714"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16055714"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Nan Wu, Xiangduo Kong, Zhejian Ji, et al. 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