Bioinformatic identification of genes suppressing genome instability

Abstract

Unbiased forward genetic screens for mutations causing increased gross chromosomal rearrangement (GCR) rates in Saccharomyces cerevisiae are hampered by the difficulty in reliably using qualitative GCR assays to detect mutants with small but significantly increased GCR rates. We therefore developed a bioinformatic procedure using genome-wide functional genomics screens to identify and prioritize candidate GCR-suppressing genes on the basis of the shared drug sensitivity suppression and similar genetic interactions as known GCR suppressors. The number of known suppressors was increased from 75 to 110 by testing 87 predicted genes, which identified unanticipated pathways in this process. This analysis explicitly dealt with the lack of concordance among high-throughput datasets to increase the reliability of phenotypic predictions. Additionally, shared phenotypes in one assay were imperfect predictors for shared phenotypes in other assays, indicating that although genome-wide datasets can be useful in aggregate, caution and validation methods are required when deciphering biological functions via surrogate measures, including growth-based genetic interactions.

A Reversible Histone H3 Acetylation Cooperates with Mismatch Repair and Replicative Polymerases in Maintaining Genome Stability

“…We also showed that H3 K56 acetylation by Rtt109 and Asf1 is involved in the protection of DNA from 1-bp insertions, small deletions, and complex mutations ( Figures 2A and 2C ); however the effects of H3 K56 acetylation are weaker than those of H3 K56 deacetylation. Therefore, our findings indicate that in addition to controlling gene transcription and GCRs [39], [53]–[55], [87], histone acetylation and deacetylation are required for the defense against point and complex mutations.…”

“…However, our knowledge about the relationship between chromatin and spontaneous mutagenesis is very limited. Previous research has identified that yeast Asf1, Caf1, Hst3, and Rtt109-dependent H3 K56 acetylation are involved in the control of GCRs [39], [53]–[55]. Additionally, a recent study reported that SET2D-dependent H3K36me3 regulates the mismatch correction function of human MMR [58].…”

“…Previous studies have demonstrated that the yeast chromatin factors Caf1, Asf1, Hst3, and Rtt109 are involved in the suppression of GCRs [39], [53]–[55]. Furthermore, human CAF-1 has been shown to interact functionally and physically with the mismatch recognition factor MutSα and modulate MMR in cell-free extracts and reconstituted systems [56], [57].…”

A Network of Conserved Synthetic Lethal Interactions for Exploration of Precision Cancer Therapy

“…DDC, DNA Damage Checkpoint, taken from Gene Ontology (Ashburner et al, 2000). GCR Supp, Gross Chromosomal Rearrangement Suppression, lists (1) and (2) both taken from (Putnam et al, 2012). Mutator supp, Mutator suppression, taken from (Huang et al, 2003).…”

Do mutator mutations fuel tumorigenesis?

“…First, many and possibly the majority of mutations in these genes are likely to be lethal or to be disadvantageous for cell growth. Second, mutations in more than 100 genes in yeast have been shown to suppress genetic instability [62]; thus, it may be difficult to identify potential mutator variants. An extreme example of this is whether mutations of TP53, the most frequently mutated gene in human cancers, can be considered mutator alleles.…”