Disease relevance of SPT4

• Previously, we found that Rad26, the yeast Cockayne syndrome B homolog and the transcription elongation factor Spt4 mediate transcription-coupled repair of UV-induced DNA damage [1].

High impact information on SPT4

• The transcription elongation factor Spt4p antagonizes Isw1p and overcomes the Isw1p dependent pausing of RNAPII at the onset of the elongation cycle [2].
• These results, taken together with the biochemical identification of a human Spt4-Spt5 complex as a transcription elongation factor (Wada et al. 1998), provide strong evidence that these factors are important for transcription elongation in vivo [3].
• In this work, we report new genetic and biochemical studies of Spt4, Spt5, and Spt6 that reveal a role for these factors in transcription elongation [3].
• In addition, we show that spt4, spt5, and spt6 mutants themselves have phenotypes suggesting defects in transcription elongation in vivo [3].
• The drugs 6-azauracil and mycophenolic acid reduce both the elongation rate and processivity, and this processivity defect is aggravated by mutations in Spt4, TFIIS, and CTDK-1 [4].

Biological context of SPT4

• The SPT4, SPT5, and SPT6 gene products define a class of transcriptional repressors in Saccharomyces cerevisiae that are thought to function through their effects on chromatin assembly or stability [5].
• Genetic mapping showed that SPT4 is a previously unidentified gene that maps to chromosome VII, between ADE6 and CLY8 [6].
• The DNA sequence of the SPT4 gene predicts a protein product of 102 amino acids that contains four cysteine residues positioned similarly to those of zinc binding proteins [6].
• We established that evolutionarily conserved Saccharomyces cerevisiae SPT4, previously identified in genetic screens for defects in chromosome transmission fidelity (ctf), encodes a new structural component of specialized chromatin at kinetochores and heterochromatic loci, with roles in kinetochore function and gene silencing [7].
• Using a genome-wide mutagenesis approach, we found that deletion of the SPT4 gene suppresses the rad26 defect [8].

Anatomical context of SPT4

• Both spt4-138 and spt4 delta strains exhibit synergistic chromosome instability in combination with CEN DNA mutations and show in vitro defects in microtubule binding to minichromosomes [9].
• Our results suggest that the Spt4-Spt5 complex may help coordinate splicing with transcription under conditions that present kinetic challenges to spliceosome assembly or function [10].

Associations of SPT4 with chemical compounds

• These results suggest that cleavage, but not read-through, stimulation activity is responsible for all three biologic functions of S-II (i.e. suppression of 6-azauracil sensitivity, induction of the IMD2 gene, and suppression of temperature sensitivity of spt4 null mutant) [11].

Physical interactions of SPT4

• We find that Spt5 is essential for viability of S. pombe and that it interacts in vivo with S. pombe Spt4 via a central domain distinct from the Spt5 CTD [12].

Regulatory relationships of SPT4

• The Spt4p subunit of yeast DSIF stimulates association of the Paf1 complex with elongating RNA polymerase II [13].
• Only spt4 suppresses a non-Ty insertion at HIS4 [14].

Other interactions of SPT4

• We investigated relationships between three classes of these factors: (1) transcription elongation factors Spt4-Spt5, TFIIS, and Spt16; (2) the C-terminal heptapeptide repeat domain (CTD) of RNA polymerase II; and (3) protein kinases that phosphorylate the CTD and a phosphatase that dephosphorylates it [15].
• Spt4p associates with telomeres (TEL) and HMRa loci in a Sir3p-dependent manner and is required for transcriptional gene silencing [7].
• We show that a human homolog of SPT4 (HsSPT4) complements Scspt4-silencing defects and associates with ScCEN DNA in an Ndc10p-dependent manner [7].
• Spt4 modulates Rad26 requirement in transcription-coupled nucleotide excision repair [8].
• Importantly, Spt4p is required for Paf1C occupancy at ARG1 (and other genes) and for Paf1C association with Ser5-phosphorylated Pol II in cell extracts, whereas Spt4p-Pol II association is independent of Paf1C [13].

Analytical, diagnostic and therapeutic context of SPT4

• Sequence analysis of a DNA fragment containing the KlCOX18 gene originating from chromosome II of the yeast Kluyveromyces lactis revealed the presence of an adjacent open reading frame (ORF) for a protein exhibiting 78.4% identity with the Saccharomyces cerevisiae Spt4p [16].
• Using a genomic approach to characterize the roles of Spt4-5 in splicing, we used splicing-sensitive DNA microarrays to identify specific sets of genes that are mis-spliced in ceg1, spt4, and spt5 mutants [10].

References