{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n LAS1L is a highly conserved nucleolar protein that plays an essential role in ribosome biogenesis by mediating the processing of precursor ribosomal RNA. In particular, LAS1L is critical for the cleavage and maturation of the internal transcribed spacer 2 (ITS2) region, an indispensable step for the synthesis of the 60S ribosomal subunit and production of mature 28S rRNA."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " Functionally, LAS1L operates as part of multiprotein complexes that include factors such as PELP1, TEX10, WDR18, NOL9, and the SUMO-specific protease SENP3; the dynamic regulation of LAS1L by SUMO conjugation/deconjugation modulates its nucleolar partitioning and is essential for efficient rRNA processing."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Impairment of LAS1L function, whether by depletion or pathogenic mutation, results in the accumulation of rRNA intermediates, eliciting a p53-dependent G1 cell cycle arrest and defective cellular proliferation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}, {"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " In addition, aberrant expression of LAS1L has been observed in several cancers including castration-resistant prostate cancer and triple-negative breast cancer, where its overexpression appears to promote tumor growth and invasive properties."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its canonical role in ribosome assembly, genetic alterations in LAS1L have been linked to neurodevelopmental disorders—ranging from intellectual disability and autism spectrum traits to congenital motor neuron disease phenotypes—emphasizing its pivotal role in neuronal development and cellular homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}, {"type": "fg_f", "ref": "7"}, {"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " Moreover, alternative transcripts such as circ_LAS1L have been shown to act as molecular sponges for microRNAs, thereby modulating gene expression in cardiac fibroblasts and influencing myocardial fibrosis after infarction."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these studies underscore LAS1L as a multifunctional protein whose precise regulation is vital for rRNA processing and ribosome assembly, cell cycle progression, and cellular homeostasis. Disruption of LAS1L functions can contribute to a spectrum of human pathologies including cancer progression and neurodevelopmental disorders, thereby highlighting it as a critical molecular target for therapeutic intervention."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Elisabeth Finkbeiner, Markus Haindl, Stefan Muller "}, {"type": "b", "children": [{"type": "t", "text": "The SUMO system controls nucleolar partitioning of a novel mammalian ribosome biogenesis complex."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/emboj.2011.33"}], "href": "https://doi.org/10.1038/emboj.2011.33"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21326211"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21326211"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Christopher D Castle, Erica K Cassimere, Catherine Denicourt "}, {"type": "b", "children": [{"type": "t", "text": "LAS1L interacts with the mammalian Rix1 complex to regulate ribosome biogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Cell (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1091/mbc.E11-06-0530"}], "href": "https://doi.org/10.1091/mbc.E11-06-0530"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22190735"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22190735"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Christopher D Castle, Erica K Cassimere, Jinho Lee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Las1L is a nucleolar protein required for cell proliferation and ribosome biogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.00358-10"}], "href": "https://doi.org/10.1128/MCB.00358-10"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20647540"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20647540"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Pavlos Fanis, Nynke Gillemans, Ali Aghajanirefah, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Five friends of methylated chromatin target of protein-arginine-methyltransferase[prmt]-1 (chtop), a complex linking arginine methylation to desumoylation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Proteomics (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/mcp.M112.017194"}], "href": "https://doi.org/10.1074/mcp.M112.017194"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22872859"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22872859"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Jacob Gordon, Monica C Pillon, Robin E Stanley "}, {"type": "b", "children": [{"type": "t", "text": "Nol9 Is a Spatial Regulator for the Human ITS2 Pre-rRNA Endonuclease-Kinase Complex."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Biol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jmb.2019.07.007"}], "href": "https://doi.org/10.1016/j.jmb.2019.07.007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31288032"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31288032"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Christopher D Castle, Richa Sardana, Varada Dandekar, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Las1 interacts with Grc3 polynucleotide kinase and is required for ribosome synthesis in Saccharomyces cerevisiae."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nucleic Acids Res (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/nar/gks1086"}], "href": "https://doi.org/10.1093/nar/gks1086"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23175604"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23175604"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Russell J Butterfield, Tamara J Stevenson, Lingyan Xing, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Congenital lethal motor neuron disease with a novel defect in ribosome biogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurology (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1212/WNL.0000000000000305"}], "href": "https://doi.org/10.1212/WNL.0000000000000305"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24647030"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24647030"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "H Hu, S A Haas, J Chelly, et al. "}, {"type": "b", "children": [{"type": "t", "text": "X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Psychiatry (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/mp.2014.193"}], "href": "https://doi.org/10.1038/mp.2014.193"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25644381"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25644381"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Shannon E Weeks, Sarah C Kammerud, Brandon J Metge, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Inhibiting β-catenin disables nucleolar functions in triple-negative breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41419-021-03531-z"}], "href": "https://doi.org/10.1038/s41419-021-03531-z"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33664239"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33664239"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Karl Hackmann, Andreas Rump, Stefan A Haas, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tentative clinical diagnosis of Lujan-Fryns syndrome--A conglomeration of different genetic entities?"}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Med Genet A (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ajmg.a.37378"}], "href": "https://doi.org/10.1002/ajmg.a.37378"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26358559"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26358559"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Kien Trung Tran, Vinh Sy Le, Hoa Thi Phuong Bui, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic landscape of autism spectrum disorder in Vietnamese children."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41598-020-61695-8"}], "href": "https://doi.org/10.1038/s41598-020-61695-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32193494"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32193494"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Li-Ye Sun, Jin-Chao Zhao, Xiao-Ming Ge, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Circ_LAS1L regulates cardiac fibroblast activation, growth, and migration through miR-125b/SFRP5 pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Biochem Funct (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/cbf.3486"}], "href": "https://doi.org/10.1002/cbf.3486"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31950540"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31950540"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Monica C Pillon, Robin E Stanley "}, {"type": "b", "children": [{"type": "t", "text": "Nuclease integrated kinase super assemblies (NiKs) and their role in RNA processing."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Curr Genet (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00294-017-0749-9"}], "href": "https://doi.org/10.1007/s00294-017-0749-9"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28929238"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28929238"}]}]}]}