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Balancing repair and tolerance of DNA damage caused by alkylating agents
Alkylating agents constitute a major class of frontline chemotherapeutic drugs that inflict cytotoxic DNA damage as their main mode of action, in addition to collateral mutagenic damage, and the response of an individual to alkylates agents can vary considerably from tissue to tissue and from person to person. Expand
Global response of Saccharomyces cerevisiae to an alkylating agent.
  • S. Jelinsky, L. Samson
  • Biology, Medicine
  • Proceedings of the National Academy of Sciences…
  • 16 February 1999
DNA chip technology enables simultaneous examination of how approximately 6,200 Saccharomyces cerevisiae gene transcript levels, representing the entire genome, respond to environmental change, and it is shown that, after exposure to the alkylating agent methyl methanesulfonate, approximately 325 gene transcripts levels are increased and approximately 76 are decreased. Expand
A Systems Approach to Mapping DNA Damage Response Pathways
Interactions for which the target changed expression in wild-type cells in response to MMS but was nonresponsive in cells lacking the TF were identified and assembled into causal pathway models that provide global hypotheses of how signaling, transcription, and phenotype are integrated after damage. Expand
Regulatory Networks Revealed by Transcriptional Profiling of Damaged Saccharomyces cerevisiae Cells: Rpn4 Links Base Excision Repair with Proteasomes
A large number of genes whose transcription is influenced by Rpn4p are identified, most likely via its binding to MAG1 upstream repressor sequence 2-like elements that turn out to be almost identical to the recently identified proteasome-associated control element. Expand
Systematic Discovery of In Vivo Phosphorylation Networks
An approach is developed that augments motif-based predictions with the network context of kinases and phosphoproteins, which suggests that BCLAF1 is a GSK-3 substrate and yields a 2.5-fold improvement in the accuracy with which phosphorylation networks can be constructed. Expand
Base excision repair in yeast and mammals.
How BER pathways have been studied in a wide variety of organisms (including yeasts) has shaped the current view of human BER is reviewed. Expand
A microscale in vitro physiological model of the liver: predictive screens for drug metabolism and enzyme induction.
A scalable microreactor system that fosters development of 3D-perfused micro-tissue units is described and it is shown that primary rat cells cultured in this system are substantially closer to native liver compared to cells cultured by other in vitro methods, as assessed by a broad spectrum of gene expression, protein expression and biochemical activity metrics. Expand
Crystal Structure of a Human Alkylbase-DNA Repair Enzyme Complexed to DNA Mechanisms for Nucleotide Flipping and Base Excision
The crystal structure of human 3-methyladenine DNA glycosylase complexed to a mechanism-based pyrrolidine inhibitor shows an elegant means of exposing a nucleotide for base excision as well as a network of residues that could catalyze the in-line displacement of a damaged base from the phosphodeoxyribose backbone. Expand
Molecular basis for discriminating between normal and damaged bases by the human alkyladenine glycosylase, AAG.
Mutational analyses of residues contacting the alkylated base in the crystal structures suggest that the shape of the damaged base, its hydrogen-bonding characteristics, and its aromaticity all contribute to the selective recognition of damage by AAG. Expand
ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade
Results suggest ARID1A deficiency contributes to impaired MMR and mutator phenotype in cancer, and may cooperate with immune checkpoint blockade therapy, complementing MSI-based prognosis. Expand