MAU2 and NIPBL Variants Impair the Heterodimerization of the Cohesin Loader Subunits and Cause Cornelia de Lange Syndrome

Parenti, I. ; Diab, F. ; Gil, S.R. ; Mulugeta, E. ; Casa, V. ; Berutti, R. ; Brouwer, R.W.W. ; Dupé, V. ; Eckhold, J. ; Graf, E. ; Puisac, B. (Universidad de Zaragoza) ; Ramos, F. (Universidad de Zaragoza) ; Schwarzmayr, T. ; Gines, M.M. ; van Staveren, T. ; van IJcken, W.F.J. ; Strom, T.M. ; Pié, J. (Universidad de Zaragoza) ; Watrin, E. ; Kaiser, F.J. ; Wendt, K.S.

Resumen: The NIPBL/MAU2 heterodimer loads cohesin onto chromatin. Mutations in NIPBL account for most cases of the rare developmental disorder Cornelia de Lange syndrome (CdLS). Here we report a MAU2 variant causing CdLS, a deletion of seven amino acids that impairs the interaction between MAU2 and the NIPBL N terminus. Investigating this interaction, we discovered that MAU2 and the NIPBL N terminus are largely dispensable for normal cohesin and NIPBL function in cells with a NIPBL early truncating mutation. Despite a predicted fatal outcome of an out-of-frame single nucleotide duplication in NIPBL, engineered in two different cell lines, alternative translation initiation yields a form of NIPBL missing N-terminal residues. This form cannot interact with MAU2, but binds DNA and mediates cohesin loading. Altogether, our work reveals that cohesin loading can occur independently of functional NIPBL/MAU2 complexes and highlights a novel mechanism protective against out-of-frame mutations that is potentially relevant for other genetic conditions.

Idioma: Inglés

DOI: 10.1016/j.celrep.2020.107647

Año: 2020

Publicado en: Cell Reports 31, 7 (2020), 107647 [22 pp]
ISSN: 2211-1247

Factor impacto JCR: 9.423 (2020)

Categ. JCR: CELL BIOLOGY rank: 33 / 195 = 0.169 (2020) - Q1 - T1

Factor impacto SCIMAGO: 6.264 - Biochemistry, Genetics and Molecular Biology (miscellaneous) (Q1)

Tipo y forma: Artículo (Versión definitiva)

Área (Departamento): Área Fisiología (Dpto. Farmac.Fisiol.y Med.L.F.)
Área (Departamento): Área Pediatría (Dpto. Microb.Ped.Radio.Sal.Pú.)