Characterization of HRG22, a human homologue of the putative tumor suppressor gene HIC1.

Database searches identified on chromosome 22q11.2, a region subject to translocations, an homologue of the HIC1 (hypermethylated in cancer) candidate tumor suppressor gene located at 17p13.3. This gene was termed HRG22 for HIC1-related gene on chromosome 22. We have characterized a new HRG22 upstream coding exon and defined the complete coding sequence of the human and zebrafish HRG22 genes. Alignment of the HRG22 and HIC1 proteins from various species revealed high sequence homology in their N-terminal BTB/POZ and five C-terminal C(2)H(2) zinc finger domains and highlighted a conserved GLDLSKK/R peptide in their middle region. The full-length HRG22 and HIC1 proteins colocalize onto nuclear dots and share several functional properties since their BTB/POZ domains heterodimerize and are autonomous transcriptional repression domain insensitive to Trichostatin A, a histone deacetylase (HDAC) inhibitor. Thus, HIC1 and HRG22 define a subgroup of BTB/POZ domains unable to recruit repressing complexes containing an HDAC activity.

Identification in the human candidate tumor suppressor gene HIC-1 of a new major alternative TATA-less promoter positively regulated by p53.

HIC-1 (hypermethylated in cancer 1), a BTB/POZ transcriptional repressor, was isolated as a candidate tumor suppressor gene located at 17p13.3, a region hypermethylated or subject to allelic loss in many human cancers and in the Miller-Dieker syndrome. The human HIC-1 gene is composed of two exons, a short 5'-untranslated exon and a large second coding exon. Recently, two murine HIC-1 isoforms generated by alternative splicing have been described. To determine whether such isoforms also exist in human, we have further analyzed the human HIC-1 locus. Here, we describe and extensively characterize a novel alternative noncoding upstream exon, exon 1b, associated with a major GC-rich promoter. We demonstrate using functional assays that the murine exon 1b previously described as coding from computer analyses of genomic sequences is in fact a noncoding exon highly homologous to its human counterpart. In addition, we report that the human untranslated exon is presumably a coding exon, renamed exon 1a, both in mice and humans. Both types of transcripts are detected in various normal human tissues with a predominance for exon 1b containing transcripts and are up-regulated by TP53, confirming that HIC-1 is a TP53 target gene. Thus, HIC-1 function in the cell is controlled by a complex interplay of transcriptional and translational regulation, which could be differently affected in many human cancers.