A human homolog of the S.cerevisiae HIR1 and HIR2 transcriptional repressors cloned from the DiGeorge syndrome critical region

Abstract

The DiGeorge syndrome (DGS) is a developmental disorder affecting derivatives of the third and fourth pharyngeal pouches. DGS patients present an interstitial deletion in one of their two chromosomes 22. Cosmid DAC30 was mapped to the DGS smallest critical region. Iterative cDNA library screening initiated with a DAC30 gene fragment candidate yielded a cDNA contig whose assembled nucleotide sequence is consistent with the widely transcribed, 4.2-4.4 kb long, messengers detected by northern analysis. The deduced protein sequence, 1017 amino acids in length, entirely encompasses the 766 amino acids previously designated as TUPLE1. The completed protein has been renamed HIRA because it contains various features matching those found in HIR1 and HIR2, two repressors of histone gene transcription characterized in the yeast Saccharomyces cerevisiae. Strikingly alike in their N-terminal third, HIRA and HIR1 contain seven copies of the WD repeat, a motif implicated in protein-protein interactions, suggesting that they might define a new subfamily of functionally homologous proteins. The remainder of the human polypeptide highly resembles a corresponding fragment in HIR2. We propose that HIRA, alone, could have a part in mechanisms of transcriptional regulation similar to that played by HIR1 and HIR2 together. The presence of a single copy of the HIRA gene in DGS patients possibly accounts for some of the abnormalities associated with this syndrome.

A Complex Composed of Tup1 and Ssn6 Represses Transcription in Vitro

“…These WD repeat repressor proteins turn off a wide variety of genes, including those involved in segmentation, sex determination, and neurogenesis (controlled by groucho) and those involved in photomorphogenesis (controlled by COP1) (7, 11). The HIRA protein has been implicated in the human developmental disease DiGeorge syndrome (8,9).Of these WD repeat repressor proteins, Tup1 is the best characterized. Tup1 along with another protein, Ssn6, is required for the repression of at least five sets of genes in yeast, including the glucose-repressed genes, genes regulated by the presence of oxygen (hypoxic genes), the a-specific and haploidspecific genes, and a set of genes induced by DNA damage (12-16).…”

“…These WD repeat repressor proteins turn off a wide variety of genes, including those involved in segmentation, sex determination, and neurogenesis (controlled by groucho) and those involved in photomorphogenesis (controlled by COP1) (7, 11). The HIRA protein has been implicated in the human developmental disease DiGeorge syndrome (8,9).…”

“…However, an increasing number of WD repeat proteins have been identified that are nuclear localized and function in the repression of transcription. These include Tup1, Hir1, and Met30 in S. cerevisiae; SCON2 in Neurospora crassa; extra sex combs and groucho in Drosophila; COP1 in Arabidopsis thaliana; and HIRA and the family of TLE proteins in humans (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). These WD repeat repressor proteins turn off a wide variety of genes, including those involved in segmentation, sex determination, and neurogenesis (controlled by groucho) and those involved in photomorphogenesis (controlled by COP1) (7,11).…”

Identical sequences but different expression patterns of Hira gene in gynogenetic and gonochoristic crucian carps

“…However, the exact function of Hira genes in higher eukaryotes still remains unclear. The predicted mammalian HIRA protein is characterized by the presence of seven N-terminal WD repeats, two bipartite nuclear localization signals, and a penta-Q stretch (Lamour et al 1995). In this paper, the full-length cDNA sequence of Hira genes has been isolated from fullymatured ovary SMART cDNA libraries of gyno-carp and gono-carp.…”

“…Mutagenesis studies have shown that null Hira mutated embryos display abnormal patterning of most developing tissues, particularly those of mesendodemal origin (Roberts et al 2002). In humans, the gene is found at chromosome 22q11, within a locus encompassing a critical region associated with the developmental disorder DiGeorge syndrome (DGS), or velocardiofacial syndrome (Lamour et al 1995;Carlson et al 1997). Xenopus HIRA has been shown to be critical for a replicationindependent nucleosome assembly pathway (RayGallet et al 2002).…”