Mislocalization of human transcription factor MOK2 in the presence of pathogenic mutations of lamin A/C.
BACKGROUND
hsMOK2 (human MOK2) is a DNA-binding transcriptional repressor. For example, it represses the IRBP (interphotoreceptor retinoid-binding protein) gene by competing with the CRX (cone-rod homeobox protein) transcriptional activator for DNA binding. Previous studies have shown an interaction between hsMOK2 and nuclear lamin A/C. This interaction could be important to explain hsMOK2 ability to repress transcription.


RESULTS
In the present study, we have tested whether missense pathogenic mutations of lamin A/C, which are located in the hsMOK2-binding domain, could affect the interaction with hsMOK2. We find that none of the tested mutations is able to disrupt hsMOK2 binding in vitro or in vivo. However, we observe an aberrant cellular localization of hsMOK2 into nuclear aggregates when pathogenic lamin A/C mutant proteins are expressed.


CONCLUSIONS
These results indicate that pathogenic mutations in lamin A/C lead to sequestration of hsMOK2 into nuclear aggregates, which may deregulate MOK2 target genes.
Dreuillet
Caroline
C
CNRS-FRE2937, Institut André Lwoff, 7 rue Guy Môquet, 94801 Villejuif, France.
Harper
Maryannick
M
Tillit
Jeanne
J
Kress
Michel
M
Ernoult-Lange
Michèle
M
D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D034904:Lamin Type A / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; D034904:Lamin Type A; D011993:Recombinant Fusion Proteins; C484253:ZNF239 protein, human; C440308:lamin C