title: Cornelia de Lange syndrome mutations in SMC1A or SMC3 affect binding to DNA.
abstract: 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 approximately 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.
authors.affiliation: Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, USA.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Revenkova
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Focarelli
authors.forename: Lucia
authors.initials: L
authors.lastname: Susani
authors.forename: Marianna
authors.initials: M
authors.lastname: Paulis
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Bassi
authors.forename: Linda
authors.initials: L
authors.lastname: Mannini
authors.forename: Annalisa
authors.initials: A
authors.lastname: Frattini
authors.forename: Domenico
authors.initials: D
authors.lastname: Delia
authors.forename: Ian
authors.initials: I
authors.lastname: Krantz
authors.forename: Paolo
authors.initials: P
authors.lastname: Vezzoni
authors.forename: Rolf
authors.initials: R
authors.lastname: Jessberger
authors.forename: Antonio
authors.initials: A
authors.lastname: Musio
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D011508:Chondroitin Sulfate Proteoglycans / Q000235:genetics / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003635:De Lange Syndrome / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D009154:Mutation; D011485:Protein Binding; D000097722:Cohesins; D000098550:Structural Maintenance of Chromosome Protein 1
chemical_list: D018797:Cell Cycle Proteins; D011508:Chondroitin Sulfate Proteoglycans; D002868:Chromosomal Proteins, Non-Histone; D004247:DNA; D004268:DNA-Binding Proteins; D000097722:Cohesins; D000098550:Structural Maintenance of Chromosome Protein 1; C492318:SMC3 protein, human