title: Impaired p32 regulation caused by the lymphoma-prone RECQ4 mutation drives mitochondrial dysfunction.
abstract: Mitochondrial DNA (mtDNA) encodes proteins that are important for ATP biogenesis. Therefore, changes in mtDNA copy number will have profound consequences on cell survival and proliferation. RECQ4 DNA helicase participates in both nuclear DNA and mtDNA synthesis. However, the mechanism that balances the distribution of RECQ4 in the nucleus and mitochondria is unknown. Here, we show that RECQ4 forms protein complexes with Protein Phosphatase 2A (PP2A), nucleophosmin (NPM), and mitochondrial p32 in different cellular compartments. Critically, the interaction with p32 negatively controls the transport of both RECQ4 and its chromatin-associated replication factor, MCM10, from the nucleus to mitochondria. Amino acids that are deleted in the most common cancer-associated RECQ4 mutation are required for the interaction with p32. Hence, this RECQ4 mutant, which is no longer regulated by p32 and is enriched in the mitochondria, interacts with the mitochondrial replication helicase PEO1 and induces abnormally high levels of mtDNA synthesis.
authors.affiliation: Department of Radiation Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010-3000, USA.
authors.forename: Jiin-Tarng
authors.initials: JT
authors.lastname: Wang
authors.affiliation: Department of Radiation Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010-3000, USA.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA 91010-3000, USA.
authors.forename: Aileen Y
authors.initials: AY
authors.lastname: Alontaga
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA 91010-3000, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Radiation Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010-3000, USA. Electronic address: yiliu@coh.org.
authors.forename: Yilun
authors.initials: Y
authors.lastname: Liu
mesh_terms: D002352:Carrier Proteins; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D004272:DNA, Mitochondrial / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008223:Lymphoma / Q000378:metabolism / Q000473:pathology; D055442:Metabolome; D064110:Minichromosome Maintenance Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000090243:Nucleophosmin; D011485:Protein Binding; D060066:Protein Interaction Maps; D054648:Protein Phosphatase 2 / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D053484:RecQ Helicases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C087299:C1QBP protein, human; D002352:Carrier Proteins; D004272:DNA, Mitochondrial; C489613:MCM10 protein, human; D024101:Mitochondrial Proteins; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D000090243:Nucleophosmin; D054648:Protein Phosphatase 2; C506731:RECQL4 protein, human; D064110:Minichromosome Maintenance Proteins; D053484:RecQ Helicases
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