Bioinformatic analyses of genome wide nucleotideexcision repair datasets in Saccharomyces cerevisiae [Abstract]
Mutagenesis(2012)
摘要
DNA is not chemically inert but faces constant challenges to its
stability. One of these is the fusion of adjacent pyrimidine
bases by ultra violet (UV) radiation to create cyclobutane
pyrimidine dimers (CPDs). Numerous methods of DNA repair
have evolved within cells, of which nucleotide excision repair
(NER) is responsible for the removal of CPDs and other bulky
adducts. To investigate this and other repair pathways various
techniques have been developed to detect DNA damage at low
resolutions in whole genomes or high resolutions over small
sections of a genome. We have developed a novel microarray
based method for the genome wide high resolution analysis of
DNA damage in yeast which combines the advantages of these,
allowing detailed measurement of repair across entire genomes.
A program has been written to predict the expected CPD
formation based on sequence; this has shown that the genome
wide damage detection method is accurate. Additionally, ChIPchip
has been used to determine the binding positions of
proteins involved in NER and analyse histone modifications
after damage induction. Combining these datasets allows
protein binding and acetylation levels to be correlated with
repair rates. These datasets require bioinformatic tools to
analyse and extract results. I have developed a suite of novel tools to process, normalise, display and interrogate these datasets including a new normalisation method which allows accurate comparisons to be made between different factors,
revealing changes in acetylation profiles following UV and
between different mutant strains, a peak detection method to
distinguish protein binding peaks from a background of nonbound regions, revealing many novel binding sites for proteins such as Abf1 and Rad16, and graphical displays to determine patterns that occur at multiple positions throughout genomes, revealing patterns of varying repair rates at regions such as centromeres and telomeres.
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