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Environmental Factor, December 2012

Intramural papers of the month

By Nisha Cavanaugh, Melissa Kerr, Anshul Pandya, and Bhargavi Rao

RAP80 reduces cancer risk and maintains genome stability

In a study published in the journal Cancer Research, NIEHS scientists reported that RAP80, a ubiquitin interaction motif-containing protein and member of the BRCA1 complex, was important in maintaining genomic stability and reducing cancer risk. Since mutations in BRCA1 and BRCA2 account for 5 to 7 percent of familial breast cancers, this study has significant implications in understanding how disruption of this complex may exacerbate the risk of developing cancer.

Using a RAP80-null mouse model developed in the NIEHS Cell Biology Group led by Anton Jetten, Ph.D., the scientists demonstrated that in the absence of RAP80, mice exposed to ionizing radiation and the carcinogen 7,12-dimethylbenz(a)anthracene had a greater tendency to develop lymphomas and mammary cancer, in addition to breast cancer. The mice lacking RAP80 also exhibited greater genomic instability, due to a reduced ability of the cells to repair genetic lesions caused by the DNA-damaging agents.

Since RAP80 has not been convincingly implicated in playing a major role in human cancers thus far, this study is critical in delineating RAP80 as a molecular marker, mutations in which can increase the risk of cancer. In addition, these mice might provide an additional model to analyze the tumorigenicity of environmental chemicals. (BR)

CitationYin Z, Menendez D, Resnick MA, French JE, Janardhan KS, Jetten AM. 2012. RAP80 is critical in maintaining genomic stability and suppressing tumor development. Cancer Res 72(19):5080-5090

DNA sequence context influences human 8-oxoguanine DNA glycosylase activity

NIEHS researchers have examined to what extent DNA sequence context affects the glycosylase activity of human 8-oxoguanine (8-oxoG) DNA glycosylase (OGG1), a part of the base excision DNA repair (BER) pathway. They discovered that mispairs positioned 5´ to the 8-oxoG lesion deter its repair and could increase 8-oxoG mutagenicity.

The research addressed a potential cause of the G to T mutational hotspot found in the human p53 gene, corresponding to a CpG dinucleotide. The G to T mutation is characteristic of oxidative stress-induced 8-oxoG lesions and their error-prone replicative bypass. Cells protect against this mutation by several processes, one of which is BER initiated by OGG1. The aim of the research was to understand the significance of methylated C adjacent to the 8-oxoG lesion on OGG1 activity.

The researchers found that OGG1 had comparable activity on DNA with 5-methyl C and normal C located 5´ to 8-oxoG. However, a mismatch placed 5´, not 3´, to the 8-oxoG lesion dramatically decreased OGG1 activity. Since methylation of C in the CpG dinucleotide leads to the T:G mispair, the results have interesting biological implications. A methylation-induced T:G mispair 5´ to the lesion can lower the opportunity for 8-oxoG removal resulting in more mutations. (NC)

CitationSassa A, Beard WA, Prasad R, Wilson SH.  2012. DNA sequence context effects on the glycosylase activity of human 8-oxoguanine DNA glycosylase. J Biol Chem 287(44):36702-36710.

Glucocorticoid signaling could lead to better therapeutics

NIEHS scientists have determined that glucocorticoids modulate the signaling profile of G protein-coupled receptors (GPCRs) through alterations in arrestin gene expression. Since GPCRs are targeted by nearly half of all prescription drugs, the work could result in the development of specific treatments that will reduce side effects and boost efficacy.

The activity of GPCRs is governed by a group of adaptor proteins called arrestins. Using several different cell types, the research team discovered that glucocorticoids directly regulate arrestin gene expression. The signaling protein beta-arrestin-1 is upregulated, while beta-arrestin-2 is downregulated. Both of these deviations occur at the transcriptional level by the binding of glucocorticoid receptors to intragenic glucocorticoid response elements. The fluctuation in arrestin expression can modify the effect GPCRs can have on human cells by biasing their signaling profile to favor G protein-dependent or beta-arrestin-dependent responses.

This discovery shows a deeper understanding of how glucocorticoids adjust responses within a cell through the regulation of the beta-arrestin gene expression, and suggest that coadministration of glucocorticoids may help or hinder the efficacy of GPCR-based treatments. (MK)

CitationOakley RH, Revollo J, Cidlowski JA. 2012. Glucocorticoids regulate arrestin gene expression and redirect the signaling profile of G protein-coupled receptors. Proc Natl Acad Sci U S A 109(43):17591-17596.

Bacteria in house dust worsens asthma

A recent study published by NIEHS scientists found that flagellin (FLA), a bacterial protein found in house dust, exacerbates asthma by inducing allergic responses to allergens. The findings reinforce the connection between asthma and the environment.

Previous studies have implicated the exposure to indoor allergens as a risk factor for asthma, so the researchers allowed mice to inhale proteins of bacterial origin or extracts of house dust, together with innocuous chicken ovalbumin (OVA). Control mice receiving either OVA alone or microbial products alone did not become sensitized and failed to develop airway inflammation after subsequent challenge with OVA. However, inhalation of FLA or house dust extracts containing FLA together with OVA caused the mice to develop allergic pulmonary inflammation following OVA challenge.

The research team also found that the mammalian receptor for FLA, toll-like receptor 5 (TLR5), was required for priming of strong allergic responses in mice by some house dust extracts. This finding was confirmed in a human study, which detected higher serum levels of FLA-specific antibodies in asthma patients compared to non-asthmatics.

The study concluded that household FLA promotes the development of allergic asthma by TLR5-dependent priming of allergic responses to indoor allergens. (AP)

CitationWilson RH, Maruoka S, Whitehead GS, Foley JF, Flake GP, Sever ML, Zeldin DC, Kraft M, Garantziotis S, Nakano H, Cook DN. 2012. The Toll-like receptor 5 ligand flagellin promotes asthma by priming allergic responses to indoor allergens. Nat Med 18(11):1705-1710.

(Nisha Cavanaugh, Ph.D., is a postdoctoral fellow in the NIEHS Laboratory of Structural Biology. Melissa Kerr studies chemistry at North Carolina Central University and is an intern in the NIEHS Office of Communications and Public Liaison. Anshul Pandya, Ph.D., is an Intramural Research Training Award (IRTA) fellow in the NIEHS Laboratory of Neurobiology. Bhargavi Rao, Ph.D., is an IRTA fellow in the NIEHS Laboratory of Molecular Carcinogenesis.)

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