Genome Profiling for Aflatoxin B Resistance in Reveals a Role for the CSM2/SHU Complex in Tolerance of Aflatoxin B-Associated DNA Damage.

Exposure to the mycotoxin aflatoxin B1 (AFB) strongly correlates with hepatocellular carcinoma (HCC). P450 enzymes convert AFB into a highly reactive epoxide that forms unstable 8,9-dihydro-8-(7-guanyl)-9-hydroxyaflatoxin B1 (AFB--Gua) DNA adducts, which convert to stable mutagenic AFB formamidopyrimidine (FAPY) DNA adducts. In CYP1A2-expressing budding yeast, AFB is a weak mutagen but a potent recombinagen.

An in vitro system for measuring genotoxicity mediated by human CYP3A4 in Saccharomyces cerevisiae.

P450 activity is required to metabolically activate many chemical carcinogens, rendering them highly genotoxic. CYP3A4 is the most abundantly expressed P450 enzyme in the liver, accounting for most drug metabolism and constituting 50% of all hepatic P450 activity. CYP3A4 is also expressed in extrahepatic tissues, including the intestine.

CYP1A1 I462V polymorphism is associated with reduced genotoxicity in yeast despite positive association with increased cancer risk.

CYP1A1 functions in detoxifying xenobiotics but occasionally converts compounds into potent genotoxins. CYP1A1 activates polyaromatic hydrocarbons, such as benzo[a]pyrene 7,8 dihydrodiol (BaP-DHD), rendering them genotoxic. Particular alleles of CYP1A1, such as CYP1A1 I462V have been correlated with a higher incidence of breast and lung cancer, but it is unknown whether these variants express enzymes in vivo that are more potent in generating genotoxins.

Activation of aflatoxin B1 by expression of human CYP1A2 polymorphisms in Saccharomyces cerevisiae.

Human susceptibility to environmental carcinogens is highly variable and depends on multiple genetic factors, including polymorphisms in cytochrome P450 genes. Although epidemiological studies have identified individual polymorphisms in cytochrome P450 genes that may alter cancer risk, there is often conflicting data about whether such polymorphisms alter the genotoxicity of environmental carcinogens. This is particularly true of the CYP1A2 polymorphisms that confer differential activation of multiple human carcinogens.

The Saccharomyces cerevisiae PDS1 and RAD9 checkpoint genes control different DNA double-strand break repair pathways.

In response to DNA damage, the Saccharomyces cerevisiae securin Pds1 blocks anaphase promotion by inhibiting ESP1-dependent degradation of cohesins. PDS1 is positioned downstream of the MEC1- and RAD9-mediated DNA damage-induced signal transduction pathways. Because cohesins participate in postreplicative repair and the pds1 mutant is radiation sensitive, we identified DNA repair pathways that are PDS1-dependent.