Cornelia de Lange syndrome mutations in SMC1A or SMC3 affect binding to DNA

Cornelia de Lange syndrome (CdLS) is a clinically heterogeneous developmental disorder characterized by facial dysmorphia, upper limb malformations, growth and cognitive retardation. Mutations in the sister chromatid cohesion factor genes NIPBL, SMC1A and SMC3 are present in ∼65% of CdLS patients. I...

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Bibliographic Details
Published in:Human molecular genetics 2009-02, Vol.18 (3), p.418-427
Main Authors: Revenkova, Ekaterina, Focarelli, Maria Luisa, Susani, Lucia, Paulis, Marianna, Bassi, Maria Teresa, Mannini, Linda, Frattini, Annalisa, Delia, Domenico, Krantz, Ian, Vezzoni, Paolo, Jessberger, Rolf, Musio, Antonio
Format: Article
Language:English
Subjects:
Biological and medical sciences
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Cell Line
Cells, Cultured
Chondroitin Sulfate Proteoglycans - genetics
Chondroitin Sulfate Proteoglycans - metabolism
Chromosomal Proteins, Non-Histone - genetics
Chromosomal Proteins, Non-Histone - metabolism
Cohesins
De Lange Syndrome - genetics
De Lange Syndrome - metabolism
DNA - genetics
DNA - metabolism
DNA Damage
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Female
Fundamental and applied biological sciences. Psychology
Genetics of eukaryotes. Biological and molecular evolution
Humans
Malformations of the nervous system
Medical sciences
Molecular and cellular biology
Mutation
Neurology
Protein Binding
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Summary:Cornelia de Lange syndrome (CdLS) is a clinically heterogeneous developmental disorder characterized by facial dysmorphia, upper limb malformations, growth and cognitive retardation. Mutations in the sister chromatid cohesion factor genes NIPBL, SMC1A and SMC3 are present in ∼65% of CdLS patients. In addition to their canonical roles in chromosome segregation, the cohesin proteins are involved in other biological processes such as regulation of gene expression, DNA repair and maintenance of genome stability. To gain insights into the molecular basis of CdLS, we analyzed the affinity of mutated SMC1A and SMC3 hinge domains for DNA. Mutated hinge dimers bind DNA with higher affinity than wild-type proteins. SMC1A- and SMC3-mutated CdLS cell lines display genomic instability and sensitivity to ionizing radiation and interstrand crosslinking agents. We propose that SMC1A and SMC3 CdLS mutations affect the dynamic association between SMC proteins and DNA, providing new clues to the underlying molecular cause of CdLS.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddn369