title: MCPH1 patient cells exhibit delayed release from DNA damage-induced G2/M checkpoint arrest.
abstract: Mutations in the MCPH1 gene cause primary microcephaly associated with a unique cellular phenotype of misregulated chromosome condensation. The encoded protein contains three BRCT domains, and accumulating data show that MCPH1 is involved in the DNA damage response. However, most of this evidence has been generated by experiments using RNA interference (RNAi) and cells from non-human model organisms. Here, we demonstrate that patient-derived cell lines display a proficient G2/M checkpoint following ionizing irradiation (IR) despite homozygous truncating mutations in MCPH1. Moreover, chromosomal breakage rates and the relocation to DNA repair foci of several proteins functioning putatively in an MCPH1-dependent manner are normal in these cells. However, the MCPH1-deficient cells exhibit a slight delay in re-entering mitosis and delayed resolution of γH2AX foci following IR. Analysis of chromosome condensation behavior following IR suggests that these latter observations may be related to hypercondensation of the chromatin in cells with MCPH1 mutations. Our results indicate that the DNA damage response in human cells with truncating MCPH1 mutations differs significantly from the damage responses in cells of certain model organisms and in cells depleted of MCPH1 by RNAi. These subtle effects of human MCPH1 deficiency on the cellular DNA damage response may explain the absence of cancer predisposition in patients with biallelic MCPH1 mutations.
authors.affiliation: Institut für Humangenetik, Universität Würzburg, Würzburg, Germany.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Gavvovidis
authors.forename: Charlotte
authors.initials: C
authors.lastname: Pöhlmann
authors.forename: Juan Alberto
authors.initials: JA
authors.lastname: Marchal
authors.forename: Markus
authors.initials: M
authors.lastname: Stumm
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yamashita
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Hirano
authors.forename: Detlev
authors.initials: D
authors.lastname: Schindler
authors.forename: Heidemarie
authors.initials: H
authors.lastname: Neitzel
authors.forename: Marc
authors.initials: M
authors.lastname: Trimborn
mesh_terms: D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins; D019457:Chromosome Breakage; D003598:Cytoskeletal Proteins; D004247:DNA / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair; D020022:Genetic Predisposition to Disease; D006367:HeLa Cells; D006801:Humans; D008831:Microcephaly / Q000235:genetics; D009154:Mutation; D009369:Neoplasms / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference
chemical_list: D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; C460645:MCPH1 protein, human; D009419:Nerve Tissue Proteins; D004247:DNA