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Abstract
BackgroundThe NCOA7 gene product is an estrogen receptor associated protein that is highly similar to the human OXR1 gene product, which functions in oxidation resistance. OXR genes are conserved among all sequenced eukaryotes from yeast to humans. In this study we examine if NCOA7 has an oxidation resistance function similar to that demonstrated for OXR1. We also examine NCOA7 expression in response to oxidative stress and its subcellular localization in human cells, comparing these properties with those of OXR1.ResultsWe find that NCOA7, like OXR1 can suppress the oxidative mutator phenotype when expressed in an E. coli strain that exhibits an oxidation specific mutator phenotype. Moreover, NCOA7's oxidation resistance function requires expression of only its carboxyl-terminal domain and is similar in this regard to OXR1. We find that, in human cells, NCOA7 is constitutively expressed and is not induced by oxidative stress and appears to localize to the nucleus following estradiol stimulation. These properties of NCOA7 are in striking contrast to those of OXR1, which is induced by oxidative stress, localizes to mitochondria, and appears to be excluded, or largely absent from nuclei.ConclusionNCOA7 most likely arose from duplication. Like its homologue, OXR1, it is capable of reducing the DNA damaging effects of reactive oxygen species when expressed in bacteria, indicating the protein has an activity that can contribute to oxidation resistance. Unlike OXR1, it appears to localize to nuclei and interacts with the estrogen receptor. This raises the possibility that NCOA7 encodes the nuclear counterpart of the mitochondrial OXR1 protein and in mammalian cells it may reduce the oxidative by-products of estrogen metabolite-mediated DNA damage.
Highlights
The NCOA7 gene product is an estrogen receptor associated protein that is highly similar to the human OXR1 gene product, which functions in oxidation resistance
In this study we examine the ability of the nuclear coactivator NCOA7 to function in protection against oxidative DNA damage
Isolation of NCOA7 and its OXR2 domain The NCOA7 gene was found in two ways: (1) by searches for estrogen receptor associated protein [25], and (2) by genome searches using the OXR1 protein sequence as a computer probe to search the human genome for DNA sequences potentially capable of encoding OXR1 paralogs [21,22]
Summary
The NCOA7 gene product is an estrogen receptor associated protein that is highly similar to the human OXR1 gene product, which functions in oxidation resistance. In this study we examine the ability of the nuclear coactivator NCOA7 (formerly called the 140 kDa estrogen receptor associated protein or ERAP140) to function in protection against oxidative DNA damage. Protective enzymes fall into two broad categories, those that prevent oxidative DNA damage from occurring and those that repair DNA damage caused by ROS. The potential mutagenic effects of oxidized DNA bases are minimized by the DNA repair enzymes [1,7,8,9,10,11]. A third class of antimutagenic enzymes are the MutT family proteins, which react with oxidized DNA nucleotide triphosphates, 8-oxoG and 8-oxoA, converting them to monophosphates, thereby preventing their incorporation into DNA during replication [16,17]
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