Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Review BCLAF1 (BCL2-associated transcription factor 1) John Peter McPherson Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, M5S 1A8 Canada (JPM) Published in Atlas Database: June 2011 Online updated version : http://AtlasGeneticsOncology.org/Genes/BCLAF1ID43164ch6q23.html DOI: 10.4267/2042/46079 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity Transcription Two transcripts 5 kb and 3 kb in length are Other names: BTF; KIAA0164; bK211L9.1 predominantly detected, however additional variant HGNC (Hugo): BCLAF1 transcripts have been described with alternative Location: 6q23.3 promoters, cassette exons and polyadenylation sites. Local order: Orientation on minus strand, flanked by Pseudogene FAM54A and MAP7 (according to GeneLoc and NCBI None identified. Map Viewer). Note: BCLAF1 was originally identified as a protein Protein partner for adenoviral E1B 19K. Forced expression of BCLAF1 causes cell death which is reversed in the Description presence of anti-apoptotic BCL-2. BCLAF1 was At least 4 isoforms are generated by alternative reported to associate in vitro with BCL-2 and BCL2L1. splicing. Two predominant BCLAF1 forms were BCLAF1 was also reported to bind DNA and repress initially described: a longer isoform 920 amino acids in transcription. Taken together, these findings suggested length with a predicted molecular mass of 106 kDa, and a role for BCLAF1 in apoptotic signalling and a smaller isoform missing 49 amino acids (residues transcriptional repression (Kasof et al., 1999). 797-846) with a predicted molecular mass of 101 kDa Subsequent studies using BCLAF1-depleted or Bclaf1- (Kasof et al., 1999). Residues 110-126 exhibit 88% deficient cells do not reveal a critical role for BCLAF1 homology to the bZIP DNA binding domain (Kasof et in death signalling (Ziegelbauer et al., 2009; al., 1999). Residues 522-531 exhibit 80% homology to McPherson et al., 2009). Recent studies have suggested the Myb DNA binding domain (Kasof et al., 1999). roles for BCLAF1 in processes of RNA metabolism Functional evidence for both of these domains remains (Bracken et al., 2008; Sarras et al., 2010), KSHV viral to be shown. The N-terminal region (residues 3-161) of production (Ziegelbauer et al., 2009), lung BCLAF1 is arginine- and serine-rich (RS domain). The development and T cell activation (McPherson et al., C-terminal region (residues 512-913) is 59% similar to 2009; Kong et al., 2011). the C-terminal region of thyroid hormone receptor associated protein 3 (THRAP3/TRAP150). DNA/RNA Expression Description BCLAF1 is ubiquitously expressed, with high steady- The BCLAF1 gene is composed of 13 exons and spans state mRNA levels in skeletal muscle, 32989 bases. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 994 BCLAF1 (BCL2-associated transcription factor 1) McPherson JP Protein domains in BCLAF1 L and BCLAF1 S isoforms. haematopoietic cells, and various other cell lineages Bclaf1-deficient cells were found to exhibit altered (Kasof et al., 1999; McPherson et al., 2009). Steady- preferences for alternative splicing of a model substrate state levels of BCLAF1 protein fluctuate in a temporal (Sarras et al., 2010). BCLAF1 was found associated and cell-lineage dependent fashion during development with SkIP, TRAP150 and Pinin in a complex known as (McPherson et al., 2009). SNIP1. SNIP1 was found to regulate cyclin D1 mRNA Localisation processing by facilitating the recruitment of the RNA processing factor U2AF65 to cyclin D1 mRNA Bclaf1 is concentrated in punctate foci interspersed (Bracken et al., 2008). through the nucleus. In the presence of E19K and BCLAF1 has been shown to complex with the RNA conditions which trigger apoptosis, the nuclear export factor TAP/NXF1 (Sarras et al., 2010). This distribution of Bclaf1 appears to concentrate at the property has also recently been reported for TRAP150, nuclear periphery or envelope (Kasof et al., 1999; a protein showing structural similarity to BCLAF1 that Haraguchi et al., 2004). also is found in ribonucleoprotein complexes (Lee et Bclaf1 was identified as a protein component of al., 2010). TRAP150 has been shown to promote pre- interchromatin granular clusters, subnuclear structures mRNA splicing of reporter substrates and promotes that appear to serve as repositories for pre-mRNA mRNA decay in a manner that is independent of splicing factors (Misteli and Spector, 1998; Sutherland nonsense-mediated decay of mRNA (Lee et al., 2010). et al., 2001; Saitoh et al., 2004). Regulation Function Sirt1 has been shown to exert transcriptional control of BCLAF1 at the promoter level (Kong et al., 2011). The exact molecular function of BCLAF1 remains to Sirt1 was found to form a complex with the histone be defined. BCLAF1 was originally identified as acetyltransferase p300 and NF-kB transcription factor having properties of a death-inducing transcriptional Rel-A, bind the BCLAF1 promoter and suppress repressor (Kasof et al., 1999). Several subsequent BCLAF1 transcription via H3K56 deacetylation (Kong studies have expanded on the link between BCLAF1, et al., 2011). transcription and apoptosis. Depletion of BCLAF1 was BCLAF1 protein levels fluctuate according to cell reported to render cells resistant to ceramide-induced cycle position, with levels highest during the G1 phase, apoptosis (Renert et al., 2009). Protein kinase C delta- but lower during S and G2 phases (Bracken et al., mediated transactivation of p53 transcription has been 2008). BCLAF1 protein levels also fluctuate in a cell- shown to occur through the stimulation of BCLAF1 to lineage and temporal manner during differentiation of co-occupy a core promoter element in the TP53 certain tissues and organs (McPherson et al., 2009). promoter (Liu et al., 2007). A role for Bclaf1 in lung Several studies have determined that Bclaf1 is development and T cell homeostasis was demonstrated extensively phosphorylated, although the functional in Bclaf1-deficient mice (McPherson et al., 2009). significance of this modification is unclear. BCLAF1 Bclaf1 was shown to be required for the proper spatial has been proposed as a substrate of GSK-3 kinase and temporal organization of smooth muscle lineage (Linding et al., 2007). Vasopressin action in kidney cells during the saccular stage of lung development. cells has been reported to simulate BCLAF1 Bclaf1 was also shown to be critical for T cell phosphorylation (Hoffert et al., 2006). activation. The phenotype of these mice could not be BCLAF1 has been shown to be one of the cellular explained by a defect in apoptosis, furthermore Bclaf1- targets for microRNAs (miRNAs) encoded by Kaposi's deficient cells displayed no defect in cell death sarcoma-associated herpesvirus (KSHV). KSHV following exposure to various apoptotic stimuli. triggers certain acquired immune deficiency syndrome- Recent studies have implicated BCLAF1 in processes related malignancies such as Kaposi's sarcoma, primary linked to RNA metabolism. BCLAF1 contains an RS effusion lymphoma and variants of multicentric domain, a feature of many factors that facilitate pre- Castleman disease. A miRNA cluster within the KSHV mRNA splicing and mRNA processing. BCLAF1 was genome is expressed during viral latency. During found to be a component of ribonucleoprotein induction of lytic KSHV growth, inhibition of miRNAs complexes (Merz et al., 2007; Sarras et al., 2010). was associated with increased BCLAF1 expression and Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 995 BCLAF1 (BCL2-associated transcription factor 1) McPherson JP decreased KSHV virion production (Ziegelbauer et al., 2009). Implicated in Interactions X-linked recessive Emery-Dreifuss E1B 19K. By yeast two-hybrid analysis, BCLAF1 was muscular dystrophy shown to directly interact with adenoviral E1B 19K via a BH3 domain and another region immediately Note adjacent to BH3 in E1B 19K (Kasof et al., 1999). In Bclaf1 has also recently been identified as a binding vitro binding assays reported BCLAF1 associates with partner for emerin, a nuclear membrane protein that is BCL-2 and BCL2L1. mutated in X-linked recessive Emery-Dreifuss emerin. By yeast-two hybrid analysis and microtiter muscular dystrophy. Disease mutations in emerin were well binding assays, BCLAF1 was shown to directly found to disrupt the interaction of emerin with interact with emerin, a nuclear membrane protein. BCLAF1 (Haraguchi et al., 2004). Mutations that result in a loss of functional emerin Disease cause X-linked recessive Emery-Dreifuss muscular Emerin is encoded by the EMD gene located on human dystrophy. The residues of emerin required for binding X-chromosome, which when mutated, gives rise to the to BCLAF1 mapped to two regions that flank its lamin- X-linked form of Emery-Dreifuss muscular dystrophy binding domain. Two disease-causing mutations in (Bione et al., 1994). Emerin is a lamin A/C binding emerin, S54F and Delta95-99, disrupted binding to protein that participates in nuclear envelope mechanics BCLAF1. BCLAF1 and emerin were observed to co- which impact chromosome segregation, gene localize in the vicinity of the nuclear envelope expression and muscle differentiation (Liu et al., 2003; following induction of apoptosis by Fas antibody Frock et al., 2006). (Haraguchi et al., 2004). MAN1. The C-terminal domain of MAN1, a nuclear