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. 2012 Nov 23:13:664.
doi: 10.1186/1471-2164-13-664.

An S/T-Q cluster domain census unveils new putative targets under Tel1/Mec1 control

Hannah C Cheung  1 , F Anthony San Lucas, Stephanie Hicks, Kyle Chang, Alison A Bertuch, Albert Ribes-Zamora
Affiliations

An S/T-Q cluster domain census unveils new putative targets under Tel1/Mec1 control

Hannah C Cheung et al. BMC Genomics. .

Abstract

Background: The cellular response to DNA damage is immediate and highly coordinated in order to maintain genome integrity and proper cell division. During the DNA damage response (DDR), the sensor kinases Tel1 and Mec1 in Saccharomyces cerevisiae and ATM and ATR in human, phosphorylate multiple mediators which activate effector proteins to initiate cell cycle checkpoints and DNA repair. A subset of kinase substrates are recognized by the S/T-Q cluster domain (SCD), which contains motifs of serine (S) or threonine (T) followed by a glutamine (Q). However, the full repertoire of proteins and pathways controlled by Tel1 and Mec1 is unknown.

Results: To identify all putative SCD-containing proteins, we analyzed the distribution of S/T-Q motifs within verified Tel1/Mec1 targets and arrived at a unifying SCD definition of at least 3 S/T-Q within a stretch of 50 residues. This new SCD definition was used in a custom bioinformatics pipeline to generate a census of SCD-containing proteins in both yeast and human. In yeast, 436 proteins were identified, a significantly larger number of hits than were expected by chance. These SCD-containing proteins did not distribute equally across GO-ontology terms, but were significantly enriched for those involved in processes related to the DDR. We also found a significant enrichment of proteins involved in telophase and cytokinesis, protein transport and endocytosis suggesting possible novel Tel1/Mec1 targets in these pathways. In the human proteome, a wide range of similar proteins were identified, including homologs of some SCD-containing proteins found in yeast. This list also included high concentrations of proteins in the Mediator, spindle pole body/centrosome and actin cytoskeleton complexes.

Conclusions: Using a bioinformatic approach, we have generated a census of SCD-containing proteins that are involved not only in known DDR pathways but several other pathways under Tel1/Mec1 control suggesting new putative targets for these kinases.

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Figures

Figure 1
Figure 1
SCD-containing proteins in S. cerevisiae. (A) List of eleven reported SCD domains [4]. For each protein, the number of S/T-Q sites within the SCD(s) is indicated with the amino acid positions in brackets. Graphical representations of the approximate location of the SCD along the length of the protein are shown on the right with reported phosphorylation sites from UniProt. For references, see Additional file 1: Table S1 (B) Distribution of the lengths of SCD-containing proteins as compared to a log-normal distribution (p-value = 0.2855). The length of protein (x-axis) is plotted against the frequency of occurrence in either the census (black) or the yeast proteome (red). (C) A pie chart showing the proportions of SCD proteins in the census that are known or novel, apportioned by whether pS/T-Q sites are characterized within the SCD. (D) Alignment of amino acids flanking known phosphorylated S/T-Q motifs in yeast, with S/T being position 0. Each unique amino acid is given a color, with the size of letter indicating the proportion of motifs having that amino acid at the position indicated. Evidence of phosphorylation was obtained from UniProt for both reported SCDs of Tel1/Mec1 targets (left) and for all known and putative SCD domains in the census (right).
Figure 2
Figure 2
Gene Ontology terms enriched in the S. cerevisiae SCD census. A bar graph showing the percentage of SCD proteins significantly associated with Gene Ontology , processes (left), components (center) and functions term (right) as compared to the percentages of all yeast proteins (red bars) having the same associations. The significant p-values (p < 0.05) are shown as a line graph, its axis on the right.
Figure 3
Figure 3
SCD-containing proteins in the S. cerevisiae SCD census. (A) Schematic of how Tel1/Mec1 may be directing the G2, Spindle Assembly, Spindle Position checkpoints, Mitotic Exit Network, and regulation of Ace2p transcription factor and polarized morphogenesis (RAM) network. Members of these checkpoints with putative SCD domains are shown in red. (B) Schematic of cell cycle progression gene clusters that are regulated by transcription factors with putative SCDs. (C) Schematic of categories of SCD-containing proteins that are involved in DNA structure and integrity. (D) Schematic of RNApolII-related complexes whose members were identified as having SCD domains.
Figure 4
Figure 4
Gene Ontology terms enriched in the SCD census for H. sapiens. A bar graph showing the percentage of SCD proteins significantly associated with Gene Ontology , processes (left), components (center) and functions term (right) as compared to the percentages of all human proteins (red bars) having the same associations. The significant p-values (p < 0.05) are shown as a line graph, its axis on the right.
Figure 5
Figure 5
Network analysis of SCD proteins in human proteome using Ingenuity© software. Selection of networks composed of SCD proteins found using Ingenuity© software (A), transcription (B), ERK signaling (C), NFĸB signaling (D), JNK signaling (E), and RAS signaling (F).
Figure 6
Figure 6
Novel stress and metabolic response pathways with SCD-containing proteins in S. cerevisiae . The TORC1 and nutrient initiated response pathways (A) and osmotic stress response pathways (B) are shown with SCD-containing proteins in red.
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