Disease relevance of RAD26

• Recently we cloned the RAD26 gene, the Saccharomyces cerevisiae homolog of human CSB/ERCC6, a gene involved in transcription-coupled repair and the disorder Cockayne syndrome [1].
• Saccharomyces cerevisiae rad26 mutants and cells from patients suffering from the hereditary disease Cockayne syndrome display a TCR defective phenotype [2].

High impact information on RAD26

• A Rad26-Def1 complex coordinates repair and RNA pol II proteolysis in response to DNA damage [3].
• Importantly, the simultaneous deletion of both RAD26 and RAD51 led to complete abolishment of strand-specific repair during G2/M, indicating that these genes act through two independent but complementary subpathways [4].
• Here we show that, in haploids, the RAD26 gene is essential for the preferential repair of the TS during G1 [4].
• Simultaneous deletion of RPB9 and RAD26 genes completely abolishes TCR in both the coding and upstream regions, indicating that no other TCR subpathway exists in RNA polymerase II-transcribed genes [5].
• Rpb4, another non-essential subunit of RNA polymerase II, plays a dual role in regulating the two subpathways, suppressing the Rpb9 subpathway and facilitating the Rad26 subpathway [5].

Chemical compound and disease context of RAD26

• To discriminate between both possibilities, we analyzed repair of UV-induced cyclobutane pyrimidine dimers at single base resolution in yeast cells lacking RAD26, the homolog of the Cockayne syndrome B gene [2].

Biological context of RAD26

• These findings unmask a role of RAD26 and transcription-coupled repair in UV survival, indicate that transcription-coupled repair and global genome repair are partially overlapping, and provide evidence for a residual NER modality in the double mutants [1].
• A strain deleted of the RAD26 gene, which is known to be required for strand-specific NER in yeast, manifested delayed recovery of mRNA synthesis, whereas a rad28 mutant, which does not show defective strand-specific repair, showed normal kinetics of recovery [6].
• Excision repair at the level of the nucleotide in the upstream control region, the coding sequence and in the region where transcription terminates of the Saccharomyces cerevisiae MFA2 gene and the role of RAD26 [7].
• However, the Rpb9 subpathway operates more effectively in the coding region than in the region upstream of the transcription start site, whereas the Rad26 subpathway operates equally in the two regions [5].
• In addition, we found evidence for a transient Rad26 localization to active genes in response to DNA damage [8].

Associations of RAD26 with chemical compounds

• Here, we examine the role of RAD26 in the repair of DNA lesions induced upon treatment with the alkylating agent methyl methanesulfonate (MMS) [9].
• Interestingly, a synergistic increase in MMS sensitivity was observed in the rad26 Delta strain upon inactivation of NER or BER, indicating that RAD26 promotes the survival of MMS-treated cells by a mechanism that acts independently of either of these repair pathways [9].
• Disrupting RAD26 affects nucleotide excision repair of transcribed DNA irrespective of the chromatin context, resulting in similar rates of removal for individual cyclobutane pyrimidine dimers throughout the transcribed strand [2].

Physical interactions of RAD26

• Thus, Pie1 is structurally and functionally related to Rad26 and interacts with Mec1 to control checkpoints and cell proliferation [10].

Regulatory relationships of RAD26

• Using a genome-wide mutagenesis approach, we found that deletion of the SPT4 gene suppresses the rad26 defect [11].

Other interactions of RAD26

• Finally, simultaneous deletion of RAD16, RAD26, and RPB9 resulted in no detectable repair in all sites along the region analyzed [12].
• Yeast rDNA, that is transcribed by RNA polymerase I(RNA pol I), is repaired efficiently, slightly strand-specific and independently of RAD26, which has been implicated in transcription-coupled repair of the RNA pol II transcribed RPB2 gene [13].
• UV sensitivity was not altered by disruption of the S-II gene in a RAD+ (NER proficient) strain, or in rad26 (impaired in efficient transcription-coupled repair), rad7 (lacking global genome repair), or rad7 rad26 (lacking global genome repair, but having residual transcription-coupled repair capacity) mutants [14].
• 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 [8].
• We identified YDR499W as a Saccharomyces cerevisiae open reading frame with homology to several checkpoint proteins, including S. cerevisiae Rfc5p and Schizosaccharomyces pombe Rad26 [15].

References