MAU2 and NIPBL Variants Impair the Heterodimerization of the Cohesin Loader Subunits and Cause Cornelia de Lange Syndrome.
Cell Rep
; 31(7): 107647, 2020 05 19.
Article
in En
| MEDLINE
| ID: mdl-32433956
ABSTRACT
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Genetic Variation
/
Chromosomal Proteins, Non-Histone
/
Cell Cycle Proteins
/
De Lange Syndrome
/
DNA-Binding Proteins
Limits:
Humans
Language:
En
Journal:
Cell Rep
Year:
2020
Document type:
Article
Affiliation country: