{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNSMF, also known as nasal embryonic luteinizing hormone‐releasing factor (NELF), has been implicated in the proper development of the reproductive axis through its role in the migration and function of gonadotropin‐releasing hormone (GnRH) neurons. Several studies in patients with idiopathic hypogonadotropic hypogonadism (IHH) and Kallmann syndrome have screened for gene dosage and mutation abnormalities in NELF, with data suggesting that although point mutations and copy number changes are relatively uncommon compared to other genes, alterations in NSMF/NELF expression or splicing may contribute to the pathogenesis of these disorders. In vitro investigations have revealed that NSMF/NELF is predominantly nuclear, contains putative zinc finger motifs, and is differentially expressed in migratory versus postmigratory GnRH neurons, supporting the notion that it may act as a transcriptional regulator to influence neuronal migration and subsequent hypothalamic-pituitary-gonadal function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its developmental roles, NSMF has been linked to the regulation of gene transcription in diverse cellular contexts. Its involvement in maintaining RNA polymerase II dynamics has been demonstrated in studies of HIV latency, where NSMF—as part of the negative elongation factor (NELF) complex—contributes to promoter-proximal pausing, premature transcription termination, and the recruitment of transcription termination factors and corepressor complexes. Moreover, in the context of colon cancer stemness, stabilized β-catenin appears to drive the assembly of an active transcription complex by enhancing the recruitment of NSMF/NELF along with other factors such as PAF1C, underscoring its role in modulating the transcription elongation process."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nA distinct and equally critical function of NSMF has emerged in the maintenance of genomic stability under conditions of DNA replication stress. Recent research has identified NSMF as a rapid responder to stalled replication forks, where it acts as a scaffold facilitating the assembly of replication protein A (RPA) complexes with CDC5L and ATR-interacting proteins. Through this scaffolding function, NSMF is essential for proper ATR activation, RPA2 phosphorylation and ubiquitination, and an effective replication stress response. Deficiency of NSMF leads to compromised ATR signaling and a consequent increase in genomic instability in both human and mouse cells, highlighting its importance for genome maintenance and cell survival."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jennifer R Pedersen-White, Lynn P Chorich, David P Bick, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The prevalence of intragenic deletions in patients with idiopathic hypogonadotropic hypogonadism and Kallmann syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Hum Reprod (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/molehr/gan027"}], "href": "https://doi.org/10.1093/molehr/gan027"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18463157"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18463157"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Ericka Barbosa Trarbach, Milena Gurgel Teles, Elaine Maria Frade Costa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Screening of autosomal gene deletions in patients with hypogonadotropic hypogonadism using multiplex ligation-dependent probe amplification: detection of a hemizygosis for the fibroblast growth factor receptor 1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Endocrinol (Oxf) (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1365-2265.2009.03642.x"}], "href": "https://doi.org/10.1111/j.1365-2265.2009.03642.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19489874"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19489874"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Ning Xu, Balasubramanian Bhagavath, Hyung-Goo Kim, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NELF is a nuclear protein involved in hypothalamic GnRH neuronal migration."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Endocrinol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.mce.2009.11.016"}], "href": "https://doi.org/10.1016/j.mce.2009.11.016"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20025934"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20025934"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Ning Xu, Hyung-Goo Kim, Balasubramanian Bhagavath, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nasal embryonic LHRH factor (NELF) mutations in patients with normosmic hypogonadotropic hypogonadism and Kallmann syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Fertil Steril (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.fertnstert.2011.01.010"}], "href": "https://doi.org/10.1016/j.fertnstert.2011.01.010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21300340"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21300340"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Samuel D Quaynor, Lindsey Y Goldberg, Eun Kyung Ko, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Differential expression of nasal embryonic LHRH factor (NELF) variants in immortalized GnRH neuronal cell lines."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Endocrinol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.mce.2013.11.020"}], "href": "https://doi.org/10.1016/j.mce.2013.11.020"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24316376"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24316376"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Malini Natarajan, Gillian M Schiralli Lester, Chanhyo Lee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Negative elongation factor (NELF) coordinates RNA polymerase II pausing, premature termination, and chromatin remodeling to regulate HIV transcription."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M113.496489"}], "href": "https://doi.org/10.1074/jbc.M113.496489"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23884411"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23884411"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Eun Kyung Ko, Lynn P Chorich, Megan E Sullivan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "JAK/STAT signaling pathway gene expression is reduced following Nelf knockdown in GnRH neurons."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Endocrinol (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.mce.2017.10.009"}], "href": "https://doi.org/10.1016/j.mce.2017.10.009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29050862"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29050862"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Koji Aoki, Akari Nitta, Ayumi Igarashi "}, {"type": "b", "children": [{"type": "t", "text": "NELF and PAF1C complexes are core transcriptional machineries controlling colon cancer stemness."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41388-023-02930-0"}], "href": "https://doi.org/10.1038/s41388-023-02930-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38182897"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38182897"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Min Kyung Ju, Kyeong Jin Shin, Joo Rak Lee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NSMF promotes the replication stress-induced DNA damage response for genome maintenance."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nucleic Acids Res (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/nar/gkab311"}], "href": "https://doi.org/10.1093/nar/gkab311"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33963872"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33963872"}]}]}]}