Interaction of the NuA4 Complex and Chromatin Modifications with the DNA Damage Tolerance Pathway
Date
2015-06-16
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Abstract
Genomic instability can arise from the failure to repair or replicate through damaged DNA. The NuA4 histone acetyltransferase complex has been shown to function through chromatin modifications that facilitate DNA transcription and damage repair. This body of work characterizes a novel function for the NuA4 complex in promoting the DNA damage tolerance (DDT) process known as translesion synthesis (TLS). DDT is functional during S and G2 phases of the cell cycle, to allow the DNA replication machinery to bypass damaged regions. This mechanism can proceed via the "error free" template switch pathway, or by an error prone translesion synthesis polymerase. Using the model organism Saccharomyces cerevisiae, I performed genetic analyses with mutants of the NuA4 histone acetyltransferase complex and representative genes of the DDT pathway. NuA4 mutants are synergistically sensitive to the alkylating drug MMS when combined with a mutant of the EF pathway. Consistent with this observation, this mutant had a defect in replication recovery similar to when both TLS and error free branches of the pathway are lost. Lastly, the defect did not arise from aberrant transcription during DNA damage but from a failure to sufficiently modify chromatin targets (H4 and H2A.Z) when challenged with damage. Subsequent work characterizing genetic interactions with DDT has identified the INO80 complex as also having a role in error prone DDT, suggesting that factors that regulate the incorporation and removal of the histone variant H2A.Z, function together to provide a supportive chromatin environment for TLS polymerases to bypass damaged based in late S to G2 phases of the cell cycle.
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Biology--Molecular
Citation
Renaud-Young, M. (2015). Interaction of the NuA4 Complex and Chromatin Modifications with the DNA Damage Tolerance Pathway (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/26597