Environmental Factor – April 2019: Intramural papers of the month

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NTP participates in international systematic reviews meeting

One way society benefits from the vast amount of research data is through systematic reviews. A systematic review collects carefully selected studies that summarize scientific evidence to answer a specific question. Researchers in the International Collaboration for Automation of Systematic Reviews (ICASR) want to automate parts of the systematic review process, to make it rapid, accurate, and efficient, and to encourage widespread acceptance of these automated techniques.

The third ICASR meeting was held October 2017 and received funding from the National Toxicology Program (NTP). ICASR member Mary Wolfe, Ph.D., director of the NTP Office of Liaison, Policy, and Review, participated in the meeting. Attendees concluded that the most pressing needs were to develop approaches for validating currently available tools and providing increased access to curated collections of text that can be used for validation.

Although there was agreement on the increased availability of tools in automating systemic reviews, workflow feasibility and acceptance of these tools remain a challenge. The group decided that the goals for the coming year would include developing an ICASR website and creating guidelines for evaluating tools and reporting automated tasks for systematic reviews. (SK)

CitationO’Connor AM, Tsafnat G, Gilbert SB, Thayer KA, Shemilt I, Thomas J, Glasziou P, Wolfe MS. 2019. Still moving toward automation of the systematic review process: a summary of discussions at the third meeting of the International Collaboration for Automation of Systematic Reviews (ICASR). Syst Rev 8(1):57.

Cryo-EM structure reveals Rix7 functions as a molecular unfoldase

Using cryo-electron microscopy (EM), researchers at NIEHS have taken a more detailed view of the budding yeast Saccharomyces cerevisiae protein Rix7 and its two AAA domains that are critical for its unfoldase activity. Rix7 is an adenosine triphosphatase, which means it uses energy from adenosine triphosphate hydrolysis to drive ribosome assembly. Rix7 captures substrates and drives their removal from the pre-60S large ribosomal unit using a hand-over-hand mechanism for substrate unfolding. This research is the first to show that Rix7 functions as a molecular unfoldase.

The authors used cryo-EM, a method used to study macromolecular structures at an atomic level, to provide a detailed view of Rix7 and the two AAA domains. Using this procedure, they were able to visualize the two AAA domains with high resolution and found that they had an asymmetric configuration. By generating mutations in these domains, the researchers determined that they are crucial for allowing substrates to pass through them, with one domain guiding and the other acting as a motor. This work paves the way for future studies to look at other Rix7 substrates and examine the mechanism behind its unfoldase activity. (SS)

CitationLo YH, Sobhany M, Hsu AL, Ford BL, Krahn JM, Borgnia MJ, Stanley RE. 2019. Cryo-EM structure of the essential ribosome assembly AAA-ATPase Rix7. Nat Commun 10(1):513.

Higher breast cancer risk linked to older biological age

For every five years a woman’s biological age was older than her chronological age, NIEHS researchers found a 15 percent increase in her chance of developing breast cancer. Because age is a leading risk factor for breast cancer, the work may help scientists better understand who may potentially develop cancer and other age-related diseases.

The research was conducted using DNA from blood samples provided by 2,764 women in the NIEHS-led Sister Study, which seeks to identify the environmental and genetic risk factors for breast cancer in more than 50,000 women in the United States and Puerto Rico. The scientists estimated biological age using DNA methylation at specific sites across the genome. Biological age estimates from these epigenetic clocks were compared with actual chronological age.

Unlike previous research on epigenetic clocks and breast cancer risk, this study accounted for factors that could bias results, including alcohol intake, menopause status, and body fat, which are known to influence both DNA methylation and breast cancer risk. Scientists do not know how age-related changes influence breast cancer development or whether the DNA aging process can be reversed. The authors wrote that capturing biological age-related variability may be used to improve breast cancer risk prediction. (CK)

CitationKresovich JK, Xu Z, O’Brien KM, Weinberg CR, Sandler DP, Taylor JA. 2019. Methylation-based biological age and breast cancer risk. J Natl Cancer Inst; doi:10.1093/jnci/djz020 [Online 22 February 2019]. (Story)

Glucocorticoids protect against stomach cancer

NIEHS researchers have revealed that glucocorticoids, a family of anti-inflammatory steroid hormones, are essential for suppressing pathogenic stomach inflammation and may prevent the development of a pre-neoplastic state called spasmolytic polypeptide-expressing metaplasia (SPEM).

Chronic inflammation, caused by long-term infection by the bacterium Helicobacter pylori, is a prime inducer of stomach cancer. Precancerous indicators of chronic inflammation in the stomach include loss of parietal cells that secrete hydrochloric acid and SPEM development, an abnormal cell transformation in the stomach mucous membrane. Glucocorticoids are known to suppress inflammation but have not been well examined in the stomach. In this study, the researchers used mouse models to investigate the role of glucocorticoids in stomach inflammation and cancer development.

By performing adrenalectomy that surgically removes both adrenal glands, the scientists depleted circulating glucocorticoids in mice and found that they showed loss of parietal cells and formation of SPEM. Disruption of glucocorticoid signaling also led to rapid activation of proinflammatory genes and a significant increase of total leukocytes in the stomach. Among different types of leukocytes, only Cx3cr1 monocytes were required to initiate adrenalectomy-induced SPEM, which suggests that, in the absence of glucocorticoids, these monocytes are pathogenic within the stomach and may promote the formation of gastric cancer. (QY)

CitationBusada JT, Ramamoorthy S, Cain DW, Xu X, Cook DN, Cidlowski JA. 2019. Endogenous glucocorticoids prevent gastric metaplasia by suppressing spontaneous inflammation. J Clin Invest 129(3):1345–1358.

Pol epsilon catalytic domains necessary for error-free DNA replication

According to NIEHS scientists and their collaborators, DNA replication fidelity, or the ability to avoid or correct errors in newly made DNA, is dramatically reduced if the catalytic domains of DNA polymerase epsilon are missing. The finding furthers our understanding of how cells make accurate copies of DNA, a process essential for all life.

A specific class of polymerases, called the B-family, is responsible for most DNA replication, whereas other classes of polymerases have more specialized roles and are involved in DNA repair. The B-family has four polymerases — alpha, delta, epsilon, and zeta — and mutations within them can be fatal to the organism.

The scientists created several yeast strains, including one with an altered polymerase epsilon that could not build or correct DNA and one with a mutated polymerase delta that generated a specific error signature. Results indicated that a normal healthy cell used polymerase epsilon to synthesize one strand of DNA and polymerase delta to synthesize the other strand. These results also indicated that polymerase delta could synthesize both DNA strands if necessary, but it was inefficient. (KH)

CitationGarbacz MA, Cox PB, Sharma S, Lujan SA, Chabes A, Kunkel TA. 2019. The absence of the catalytic domains of Saccharomyces cerevisiae DNA polymerase epsilon strongly reduces DNA replication fidelity. Nucleic Acids Res; doi:10.1093/nar/gkz048 [Online 30 January 2019].

(Kiri Hoff, Ph.D., is an Intramural Research Training Award [IRTA] fellow in the NIEHS Mitochondrial DNA Replication Group. Carol Kelly is a technical writer and editor for the NIEHS Office of Communications and Public Liaison. Stephani Kim, Ph.D., is an IRTA fellow in the NIEHS Perinatal and Early Life Epidemiology Group. Salahuddin Syed, Ph.D., is an IRTA fellow in the NIEHS DNA Replication Fidelity Group. Qing Xu is a biologist in the NIEHS Metabolism, Genes, and Environment Group.)

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