Increased DNA damage sensitivity of Cornelia de Lange syndrome cells: evidence for impaired recombinational repair.

Details

Serval ID
serval:BIB_059EA951A1C3
Type
Article: article from journal or magazin.
Collection
Publications
Title
Increased DNA damage sensitivity of Cornelia de Lange syndrome cells: evidence for impaired recombinational repair.
Journal
Human molecular genetics
Author(s)
Vrouwe M.G., Elghalbzouri-Maghrani E., Meijers M., Schouten P., Godthelp B.C., Bhuiyan Z.A., Redeker E.J., Mannens M.M., Mullenders L.H., Pastink A., Darroudi F.
ISSN
0964-6906 (Print)
ISSN-L
0964-6906
Publication state
Published
Issued date
15/06/2007
Peer-reviewed
Oui
Volume
16
Number
12
Pages
1478-1487
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
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.

Keywords
Cells, Cultured, Chromosome Aberrations, DNA Damage, DNA Repair/physiology, De Lange Syndrome/genetics, G2 Phase, Histones/metabolism, Humans, Mitomycin/pharmacology, Nucleic Acid Synthesis Inhibitors/pharmacology, Proteins/genetics, Proteins/metabolism, Rad51 Recombinase/metabolism, Radiation, Ionizing, Recombination, Genetic
Pubmed
Web of science
Open Access
Yes
Create date
01/03/2018 15:34
Last modification date
20/08/2019 12:27
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