Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/70075
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Type: Journal article
Title: Functional characterization of the AFF (AF4/FMR2) family of RNA-binding proteins: insights into the molecular pathology of FRAXE intellectual disability
Author: Melko, M.
Douguet, D.
Bensaid, M.
Zongaro, S.
Verheggen, C.
Gecz, J.
Bardoni, B.
Citation: Human Molecular Genetics, 2011; 20(10):1873-1885
Publisher: Oxford Univ Press
Issue Date: 2011
ISSN: 0964-6906
1460-2083
Statement of
Responsibility: 
Mireille Melko, Dominique Douguet, Mounia Bensaid, Samantha Zongaro, Céline Verheggen, Jozef Gecz and Barbara Bardoni
Abstract: The AFF (AF4/FMR2) family of genes includes four members: AFF1/AF4, AFF2/FMR2, AFF3/LAF4 and AFF4/AF5q31. AFF2/FMR2 is silenced in FRAXE intellectual disability, while the other three members have been reported to form fusion genes as a consequence of chromosome translocations with the myeloid/lymphoid or mixed lineage leukemia (MLL) gene in acute lymphoblastic leukemias (ALLs). All AFF proteins are localized in the nucleus and their role as transcriptional activators with a positive action on RNA elongation was primarily studied. We have recently shown that AFF2/FMR2 localizes to nuclear speckles, subnuclear structures considered as storage/modification sites of pre-mRNA splicing factors, and modulates alternative splicing via the interaction with the G-quadruplex RNA-forming structure. We show here that similarly to AFF2/FMR2, AFF3/LAF4 and AFF4/AF5q31 localize to nuclear speckles and are able to bind RNA, having a high apparent affinity for the G-quadruplex structure. Interestingly, AFF3/LAF4 and AFF4/AF5q31, like AFF2/FMR2, modulate, in vivo, the splicing efficiency of a mini-gene containing a G-quadruplex structure in one alternatively spliced exon. Furthermore, we observed that the overexpression of AFF2/3/4 interferes with the organization and/or biogenesis of nuclear speckles. These findings fit well with our observation that enlarged nuclear speckles are present in FRAXE fibroblasts. Furthermore, our findings suggest functional redundancy among the AFF family members in the regulation of splicing and transcription. It is possible that other members of the AFF family compensate for the loss of AFF2/FMR2 activity and as such explain the relatively mild to borderline phenotype observed in FRAXE patients.
Keywords: Cell Line; Hela Cells; Intranuclear Space; Fibroblasts; Humans; Fragile X Syndrome; RNA-Binding Proteins; DNA-Binding Proteins; Sequence Alignment; Gene Expression; RNA Splicing; Amino Acid Sequence; Sequence Homology, Amino Acid; Protein Transport; Gene Order; Genes, Reporter; Molecular Sequence Data
Rights: © The Author 2011.
RMID: 0020106146
DOI: 10.1093/hmg/ddr069
Appears in Collections:Paediatrics publications

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