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

Ekaterina Revenkova, Maria Luisa Focarelli, Lucia Susani, Marianna Paulis, Maria Teresa Bassi, Linda Mannini, Annalisa Frattini, Domenico Delia, Ian Krantz, Paolo Vezzoni, Rolf Jessberger, Antonio Musio

Research output: Contribution to journalArticle

72 Citations (Scopus)

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 ∼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.

Original languageEnglish
Pages (from-to)418-427
Number of pages10
JournalHuman Molecular Genetics
Volume18
Issue number3
DOIs
Publication statusPublished - 2009

Fingerprint

De Lange Syndrome
Mutation
DNA
Genomic Instability
Biological Phenomena
Chromosome Segregation
Proteins
Chromatids
Gene Expression Regulation
Ionizing Radiation
Upper Extremity
DNA Repair
Siblings
Maintenance
Cell Line
Growth
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

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

In: Human Molecular Genetics, Vol. 18, No. 3, 2009, p. 418-427.

Research output: Contribution to journalArticle

Revenkova, E, Focarelli, ML, Susani, L, Paulis, M, Bassi, MT, Mannini, L, Frattini, A, Delia, D, Krantz, I, Vezzoni, P, Jessberger, R & Musio, A 2009, 'Cornelia de Lange syndrome mutations in SMC1A or SMC3 affect binding to DNA', Human Molecular Genetics, vol. 18, no. 3, pp. 418-427. https://doi.org/10.1093/hmg/ddn369
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. / Cornelia de Lange syndrome mutations in SMC1A or SMC3 affect binding to DNA. In: Human Molecular Genetics. 2009 ; Vol. 18, No. 3. pp. 418-427.
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AU - Focarelli, Maria Luisa

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AU - Paulis, Marianna

AU - Bassi, Maria Teresa

AU - Mannini, Linda

AU - Frattini, Annalisa

AU - Delia, Domenico

AU - Krantz, Ian

AU - Vezzoni, Paolo

AU - Jessberger, Rolf

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