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Extramural Papers

By Jerry Phelps
September 2009

"Sloppier Copier" Mysteries Solved

New discoveries by NIEHS-funded biologists solved a vexing question about the role of the protein RecA in DNA repair and determined the exact composition of the active form of the DNA repair enzyme polymerase V.

RecA is a nucleoprotein filament, which is a long line of proteins bound to a single-stranded DNA. It transfers two molecules to polymerase V resulting in the enzymes activation — ATP for fuel and a single RecA protein. Although RecA does not actively participate in the repair process, it activates polymerase V, which as a result begins walking down the damaged DNA segment copying a new strand. As soon as it reaches the end of the damaged section, it drops off the DNA and immediately deactivates. It must be reactivated by RecA to copy more DNA, in contrast to all other DNA polymerases.

In 1999, researchers in this laboratory discovered polymerase V, which was nicknamed the "sloppier copier" because it makes frequent copying mistakes that show up as mutations in the cell's DNA. The researchers postulate that polymerase V may be more important for the long-term success of a species than its more accurate counterparts because some of the mutations are likely to be helpful, enabling organisms to better adapt to their environments.

Citation: Jiang Q, Karata K, Woodgate R, Cox MM, Goodman MF(http://www.ncbi.nlm.nih.gov/pubmed/19606142?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum) Exit NIEHS. 2009. The active form of DNA polymerase V is UmuD'2C-RecA-ATP. Nature 460(7253):359-363.

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Bisphenol A Reduces the Effectiveness of Chemotherapeutics

Recent research results suggest that the environmental estrogen bisphenol A (BPA), in addition to its potential carcinogenic and reproductive health effects, reduces the effectiveness of three common chemotherapeutic agents used to treat breast cancer.

BPA is structurally similar to diethylstilbestrol (DES) and its carcinogenic potential is of strong concern to scientists and regulators. Similar to DES, BPA has estrogenic activity, and exposure in young rodents leads to increased rates of hormonally related cancers as the animal's age. Since estrogen has been shown to antagonize some anticancer drugs, the research team wanted to test BPA for its potential to reduce the effectiveness of these anticancer agents.

The findings were clear. At nanomolar concentrations of BPA, levels routinely found in humans, estrogen receptor-positive and –negative breast cancer cells lines were protected from the chemotherapeutic effects of doxorubicin, cisplatin, and vinblastine. The researchers speculate that the protective effect could be the result of increased expression of anti-apoptotic proteins caused by BPA.

This study highlights a previously unrecognized effect of BPA in carcinogenicity and therefore adds strong support to the growing knowledge of the adverse effects of BPA on human health. It also suggests that BPA exposure may be a factor in choosing therapeutic regimens in patients undergoing treatment for hormonally related cancers.

Citation: Lapensee EW, Tuttle TR, Fox SR, Ben-Jonathan N (http://www.ncbi.nlm.nih.gov/pubmed/19270784?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum) Exit NIEHS. 2009. Bisphenol A at low nanomolar doses confers chemoresistance in estrogen receptor-alpha-positive and –negative breast caner cells. Environ Health Perspect 117(2):175-180.

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Progesterone Triggers Breast Inflammation

NIEHS-funded researchers at Michigan State University report that exposure to the hormone progesterone activates genes that trigger inflammation in the mammary gland. This inflammation may be a key factor in increasing the risk of breast cancer.

Paradoxically, progesterone promotes normal development of the breast, but it has been previously identified as a risk factor for breast cancer. Exposure to progesterone in normal amounts causes breast inflammation, which leads to development. However, exposure to progesterone in post-menopausal hormone therapy is a known risk factor for breast cancer.

In a laboratory mouse study, the researchers examined genes activated by progesterone and the effects of their activation. They found that progesterone regulates 162 genes in pubertal cells, 104 genes in adult cells and 68 genes in cells during both developmental stages. Some of these genes code for small proteins called chemokines that are active in the process of inflammation.

The study identified the targets of progesterone receptor A in mammary cell development. These links provide avenues of research and potential therapies in reducing the influence progesterone has on developing breast cancer.

Citation: Santos SJ, Aupperlee MD, Xie J, Durairaj S, Miksicek R, Conrad SE, Leipprandt JR, Tan YS, Schwartz RC, Haslam SZ (http://www.ncbi.nlm.nih.gov/pubmed/19383543?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum) Exit NIEHS. 2009. Progesterone receptor A-regulated gene expression in mammary organoid cultures. J Steroid Biochem Mol Biol 115(3-5):161-172.

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Potential Discovery of New Asthma Therapy

NIEHS-funded clinical investigators discovered that a single enzyme is critical in most allergen-induced asthma attacks. The activity of the enzyme, aldose reductase, can be significantly reduced by drugs that have already undergone clinical trials for diabetes complications.

In a wide variety of diseases, including cancer, atherosclerosis, asthma and diabetes, exposure to high levels of reactive oxygen species (ROS) leads to the release of a barrage of inflammatory signaling proteins. These proteins stimulate more immune system cells to enter the affected tissue causing the release of even more ROS, producing a cycle of ever-increasing inflammation.

Aldose reductase plays a pivotal role in the activation of inflammatory processes. Knowing that asthma is a chronic disease of inflammation, the research team postulated that aldose reductase inhibition would have beneficial effects in preventing asthma exacerbations.

Experiments were carried out in cultures of human airway epithelial cells. Compared to untreated cells, cells treated with an enzyme inhibitor had a much milder inflammatory response to ragweed pollen exposure. Similar studies in live mice also showed that mice given an aldose reductase inhibitor had a dramatically reduced inflammatory response after exposure to ragweed pollen.

The research team plans to conduct clinical trials to determine whether aldose reductase inhibitors will be beneficial in treating human asthma.

Citation: Yadav UC, Ramana KV, Aguilera-Aguirre L, Boldogh I, Boulares HA, Srivastava SK (http://www.ncbi.nlm.nih.gov/pubmed/19657391?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum) Exit NIEHS. 2009. Inhibition of aldose reductase prevents experimental allergic airway inflammation in mice. PLoS One 4(8):e6535.

(Jerry Phelps is a program analyst in the NIEHS Division of Extramural Research and Training. Each month, he contributes summaries of extramural papers to the Environmental Factor.)



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