title: A novel MCPH1 isoform complements the defective chromosome condensation of human MCPH1-deficient cells.
abstract: Biallelic mutations in MCPH1 cause primary microcephaly (MCPH) with the cellular phenotype of defective chromosome condensation. MCPH1 encodes a multifunctional protein that notably is involved in brain development, regulation of chromosome condensation, and DNA damage response. In the present studies, we detected that MCPH1 encodes several distinct transcripts, including two major forms: full-length MCPH1 (MCPH1-FL) and a second transcript lacking the six 3' exons (MCPH1Δe9-14). Both variants show comparable tissue-specific expression patterns, demonstrate nuclear localization that is mediated independently via separate NLS motifs, and are more abundant in certain fetal than adult organs. In addition, the expression of either isoform complements the chromosome condensation defect found in genetically MCPH1-deficient or MCPH1 siRNA-depleted cells, demonstrating a redundancy of both MCPH1 isoforms for the regulation of chromosome condensation. Strikingly however, both transcripts are regulated antagonistically during cell-cycle progression and there are functional differences between the isoforms with regard to the DNA damage response; MCPH1-FL localizes to phosphorylated H2AX repair foci following ionizing irradiation, while MCPH1Δe9-14 was evenly distributed in the nucleus. In summary, our results demonstrate here that MCPH1 encodes different isoforms that are differentially regulated at the transcript level and have different functions at the protein level.
authors.affiliation: Department of Human Genetics, University of Würzburg, Würzburg, Germany. ioannis.gavvovidis@mdc-berlin.de
authors.forename: Ioannis
authors.initials: I
authors.lastname: Gavvovidis
authors.forename: Isabell
authors.initials: I
authors.lastname: Rost
authors.forename: Marc
authors.initials: M
authors.lastname: Trimborn
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Kaiser
authors.forename: Josephine
authors.initials: J
authors.lastname: Purps
authors.forename: Constanze
authors.initials: C
authors.lastname: Wiek
authors.forename: Helmut
authors.initials: H
authors.lastname: Hanenberg
authors.forename: Heidemarie
authors.initials: H
authors.lastname: Neitzel
authors.forename: Detlev
authors.initials: D
authors.lastname: Schindler
mesh_terms: D020816:Amino Acid Motifs; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002467:Cell Nucleus / Q000378:metabolism; D018385:Centrosome / Q000648:ultrastructure; D002843:Chromatin / Q000737:chemistry; D002875:Chromosomes / Q000648:ultrastructure; D003598:Cytoskeletal Proteins; D005091:Exons; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008957:Models, Genetic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics*; D010455:Peptides / Q000737:chemistry; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D011839:Radiation, Ionizing; D014018:Tissue Distribution
chemical_list: D018797:Cell Cycle Proteins; D002843:Chromatin; D003598:Cytoskeletal Proteins; C460645:MCPH1 protein, human; D009419:Nerve Tissue Proteins; D010455:Peptides; D020033:Protein Isoforms; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins