title: Increased DNA damage sensitivity of Cornelia de Lange syndrome cells: evidence for impaired recombinational repair.
abstract: Cornelia de Lange syndrome (CdLS) is a rare dominantly inherited multisystem disorder affecting both physical and mental development. Heterozygous mutations in the NIPBL gene were found in about half of CdLS cases. Scc2, the fungal ortholog of the NIPBL gene product, is essential for establishing sister chromatid cohesion. In yeast, the absence of cohesion leads to chromosome mis-segregation and defective repair of DNA double-strand breaks. To evaluate possible DNA repair defects in CdLS cells, we characterized the cellular responses to DNA-damaging agents. We show that cells derived from CdLS patients, both with and without detectable NIPBL mutations, have an increased sensitivity for mitomycin C (MMC). Exposure of CdLS fibroblast and B-lymphoblastoid cells to MMC leads to enhanced cell killing and reduced proliferation and, in the case of primary fibroblasts, an increased number of chromosomal aberrations. After X-ray exposure increased numbers of chromosomal aberrations were also detected, but only in cells irradiated in the G(2)-phase of the cell cycle when repair of double-strand breaks is dependent on the establishment of sister chromatid cohesion. Repair at the G(1) stage is not affected in CdLS cells. Our studies indicate that CdLS cells have a reduced capacity to tolerate DNA damage, presumably as a result of reduced DNA repair through homologous recombination.
authors.affiliation: Department of Toxicogenetics, Leiden University Medical Center, Postal Zone S-6-P, PO Box 9600, 2300 RC, Leiden.
authors.forename: Mischa G
authors.initials: MG
authors.lastname: Vrouwe
authors.forename: Elhaam
authors.initials: E
authors.lastname: Elghalbzouri-Maghrani
authors.forename: Matty
authors.initials: M
authors.lastname: Meijers
authors.forename: Peter
authors.initials: P
authors.lastname: Schouten
authors.forename: Barbara C
authors.initials: BC
authors.lastname: Godthelp
authors.forename: Zahurul A
authors.initials: ZA
authors.lastname: Bhuiyan
authors.forename: Egbert J
authors.initials: EJ
authors.lastname: Redeker
authors.forename: Marcel M
authors.initials: MM
authors.lastname: Mannens
authors.forename: Leon H F
authors.initials: LH
authors.lastname: Mullenders
authors.forename: Albert
authors.initials: A
authors.lastname: Pastink
authors.forename: Firouz
authors.initials: F
authors.lastname: Darroudi
mesh_terms: D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D004249:DNA Damage; D004260:DNA Repair / Q000502:physiology*; D003635:De Lange Syndrome / Q000235:genetics*; D016195:G2 Phase; D006657:Histones / Q000378:metabolism; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D051135:Rad51 Recombinase / Q000378:metabolism; D011839:Radiation, Ionizing; D011995:Recombination, Genetic
chemical_list: D018797:Cell Cycle Proteins; C468783:H2AX protein, human; D006657:Histones; C487465:NIPBL protein, human; D019384:Nucleic Acid Synthesis Inhibitors; D011506:Proteins; D016685:Mitomycin; D051135:Rad51 Recombinase