{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPOLA1 encodes the catalytic subunit of the DNA polymerase α–primase complex, which is essential for the initiation of eukaryotic DNA replication. This enzyme is responsible for synthesizing the RNA–DNA hybrid primers that provide the 3′ ends required for high‐processivity polymerases to carry out bulk genomic replication."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nThe activity and stability of POLA1 are tightly controlled through dynamic protein–protein interactions and transcriptional regulation. Studies have shown that POLA1 (often referred to by its p180 subunit designation) is recruited to replication origins via factors such as Mcm10, and its gene expression is subject to activation by transcription factors including Y-box proteins and CDP/Cux. These interactions and modifications play critical roles in safeguarding replication initiation and ensuring proper progression through S phase."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nStructural and enzymatic analyses have revealed that POLA1 possesses specific domains and metal‐binding motifs critical for its primer synthesis activity and fidelity. Detailed kinetic studies and crystallographic data have elucidated how POLA1 discriminates between nucleotides and engages both RNA–DNA and DNA–DNA duplex substrates. These investigations demonstrate that POLA1 employs both positive and negative selection mechanisms during catalysis and that the conformational state of its “fingers” affects substrate binding and the transition to productive catalysis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDefects in POLA1 function have been linked to impaired replication, genome instability, and aberrant cell signaling. Notably, mutations that disrupt POLA1 expression lead to increased type I interferon production and are associated with X‐linked disorders characterized by developmental delay and immunodeficiency. Moreover, chromosomal rearrangements interrupting POLA1 have been implicated in clinical phenotypes that include microcephaly and other developmental abnormalities, while functional depletion of POLA1 provokes checkpoint activation and DNA damage responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Wenge Zhu, Chinweike Ukomadu, Sudhakar Jha, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mcm10 and And-1/CTF4 recruit DNA polymerase alpha to chromatin for initiation of DNA replication."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Dev (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1101/gad.1585607"}], "href": "https://doi.org/10.1101/gad.1585607"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17761813"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17761813"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Luca Pellegrini "}, {"type": "b", "children": [{"type": "t", "text": "The Pol α-primase complex."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Subcell Biochem (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/978-94-007-4572-8_9"}], "href": "https://doi.org/10.1007/978-94-007-4572-8_9"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22918585"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22918585"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Yinbo Zhang, Andrey G Baranovskiy, Tahir H Tahirov, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The C-terminal domain of the DNA polymerase catalytic subunit regulates the primase and polymerase activities of the human DNA polymerase α-primase complex."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M114.570333"}], "href": "https://doi.org/10.1074/jbc.M114.570333"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24962573"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24962573"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Mary Truscott, Lélia Raynal, Peter Premdas, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CDP/Cux stimulates transcription from the DNA polymerase alpha gene promoter."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.23.8.3013-3028.2003"}], "href": "https://doi.org/10.1128/MCB.23.8.3013-3028.2003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12665598"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12665598"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Abdelaziz En-Nia, Emek Yilmaz, Uwe Klinge, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Transcription factor YB-1 mediates DNA polymerase alpha gene expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M413353200"}], "href": "https://doi.org/10.1074/jbc.M413353200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15615704"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15615704"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Masaharu Takemura, Shonen Yoshida, Tetsu Akiyama, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Role of the second-largest subunit of DNA polymerase alpha in the interaction between the catalytic subunit and hyperphosphorylated retinoblastoma protein in late S phase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbapap.2006.06.015"}], "href": "https://doi.org/10.1016/j.bbapap.2006.06.015"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16935576"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16935576"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Sharbani Chattopadhyay, Anja-Katrin Bielinsky "}, {"type": "b", "children": [{"type": "t", "text": "Human Mcm10 regulates the catalytic subunit of DNA polymerase-alpha and prevents DNA damage during replication."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Cell (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1091/mbc.e06-12-1148"}], "href": "https://doi.org/10.1091/mbc.e06-12-1148"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17699597"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17699597"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Eric M Warren, Hao Huang, Ellen Fanning, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Physical interactions between Mcm10, DNA, and DNA polymerase alpha."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M109.020438"}], "href": "https://doi.org/10.1074/jbc.M109.020438"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19608746"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19608746"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Mairi L Kilkenny, Giacomo De Piccoli, Rajika L Perera, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A conserved motif in the C-terminal tail of DNA polymerase α tethers primase to the eukaryotic replisome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M112.368951"}], "href": "https://doi.org/10.1074/jbc.M112.368951"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22593576"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22593576"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Molly Chiaramonte, Chad L Moore, Kristi Kincaid, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Facile polymerization of dNTPs bearing unnatural base analogues by DNA polymerase alpha and Klenow fragment (DNA polymerase I)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochemistry (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/bi034763l"}], "href": "https://doi.org/10.1021/bi034763l"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12950174"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12950174"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Jeff Beckman, Kristi Kincaid, Michal Hocek, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human DNA polymerase alpha uses a combination of positive and negative selectivity to polymerize purine dNTPs with high fidelity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochemistry (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/bi061243s"}], "href": "https://doi.org/10.1021/bi061243s"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17209555"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17209555"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Yoshiaki Suwa, Jianyou Gu, Andrey G Baranovskiy, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Crystal Structure of the Human Pol α B Subunit in Complex with the C-terminal Domain of the Catalytic Subunit."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M115.649954"}], "href": "https://doi.org/10.1074/jbc.M115.649954"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25847248"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25847248"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Javier Coloma, Robert E Johnson, Louise Prakash, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human DNA polymerase α in binary complex with a DNA:DNA template-primer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/srep23784"}], "href": "https://doi.org/10.1038/srep23784"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27032819"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27032819"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Lorena Taricani, Frances Shanahan, David Parry "}, {"type": "b", "children": [{"type": "t", "text": "Replication stress activates DNA polymerase alpha-associated Chk1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Cycle (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4161/cc.8.3.7661"}], "href": "https://doi.org/10.4161/cc.8.3.7661"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19177015"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19177015"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Petro Starokadomskyy, Terry Gemelli, Jonathan J Rios, et al. "}, {"type": "b", "children": [{"type": "t", "text": "DNA polymerase-α regulates the activation of type I interferons through cytosolic RNA:DNA synthesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Immunol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ni.3409"}], "href": "https://doi.org/10.1038/ni.3409"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27019227"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27019227"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Anna Podolska, Albrecht Kobelt, Sigrid Fuchs, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Functional monosomy of 6q27-qter and functional disomy of Xpter-p22.11 due to X;6 translocation with an atypical X-inactivation pattern."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Med Genet A (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ajmg.a.38183"}], "href": "https://doi.org/10.1002/ajmg.a.38183"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28371302"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28371302"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Hilde Van Esch, Rita Colnaghi, Kathleen Freson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Defective DNA Polymerase α-Primase Leads to X-Linked Intellectual Disability Associated with Severe Growth Retardation, Microcephaly, and Hypogonadism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2019.03.006"}], "href": "https://doi.org/10.1016/j.ajhg.2019.03.006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31006512"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31006512"}]}]}]}