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Human Molecular Genetics Advance Access originally published online on April 27, 2007
Human Molecular Genetics 2007 16(12):1478-1487; doi:10.1093/hmg/ddm098
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Mischa G. Vrouwe1, Elhaam Elghalbzouri-Maghrani1, Matty Meijers1, Peter Schouten1, Barbara C. Godthelp1, Zahurul A. Bhuiyan2, Egbert J. Redeker2, Marcel M. Mannens2, Leon H.F. Mullenders1, Albert Pastink1,* and Firouz Darroudi1,*

1 Department of Toxicogenetics, Leiden University Medical Center, Postal Zone S-6-P, PO Box 9600, 2300 RC, Leiden, The Netherlands and 2 Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands

* To whom correspondence should be addressed. Tel: +31 715269613; Fax: +31 715268284; Email: a.pastink{at}lumc.nl;(A.P.) or Tel: +31 715269612; Fax: +31 715268284; Email: f.darroudi{at}lumc.nl(F.D.)

Received January 29, 2007; Revised April 3, 2007; Accepted April 11, 2007

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 G2-phase of the cell cycle when repair of double-strand breaks is dependent on the establishment of sister chromatid cohesion. Repair at the G1 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.


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