Environmental Factor – May 2019: Leaves of the Month Outside the Walls

outside the walls
Written by Sarah Amuligbe

DNA polymerase theta protects against UV-induced cancer

NIEHS grant recipients provided evidence that theta (DNA polymerase) polymerase (pol Q) protects against ultraviolet (UV)-induced melanoma, although pol Q also increases the number of UV-induced mutations. They note that pol Q may play a protective role through a process called error-prone transformation synthesis (TLS), which allows DNA to repeat previous mutations and withstand DNA damage.

To understand the role of TLS in the formation of melanoma, the researchers used cell studies to analyze the enzymes that make DNA molecules, known as DNA polymerases, to identify the DNA polymerase responsible for generating the UV-induced mutations. In cell studies, they showed that pol Q led to increased mutagenesis caused by UV exposure and was required for the generation of certain types of mutations.

Because pol Q led to DNA mutations in cells, the scientists created a pol Q-deficient mouse model and examined susceptibility to UV-induced skin cancers. Contrary to expectations, the team found that mice deficient in pol Q were more likely to develop skin cancer from UV damage.

The team analyzed UV-damaged DNA replication in mice and discovered that mechanisms of TLS by pol Q and other polymerases prevented the breakdown of replication forks. Replication forks are active regions of DNA replication that can break down at sites of DNA damage. This can lead to genetic instability and promote tumor progression. Since TLS by pol Q prevented replication fork collapse, the authors suggested that although pol Q could induce mutations, it also provided protection against cancer formation.

the quote: Yoon JH, McArthur MJ, Park J, Basu D, Wakamiya M, Prakash L, Prakash S. 2019. Error-prone reproduction by UV lesions by theta DNA polymerase protects against skin cancers. Cell 176 (6): 1295-1309.e15.

Omega-3 and omega-6 may play an opposite role in asthma

A NIEHS-funded study found that children who had more omega-3 fatty acids found in foods like salmon had less severe asthma and fewer symptoms caused by indoor air pollution. The same study showed an opposite effect of high levels of omega-6 fatty acids found in corn oil and other foods, which have been associated with increased asthma severity and increased symptoms.

Researchers studied 135 children with asthma in Baltimore. Asthma severity and lung function were assessed at the start of the study, at three and six months. At each time point, the researchers captured week-long average household air particulate concentrations, dietary intake of omega-3 and omega-6 fatty acids, and information on daily asthma symptoms and inhaler use.

The researchers found that for every extra gram of omega-6 in their diet, the children had 29% higher odds of being in a more severe asthma category. With each 0.1 gram increase in omega-3 fatty acid intake, the researchers observed a 3-4% decrease in the odds of developing daytime asthma symptoms. In general, children who ate more omega-3s were less likely to develop symptoms even at the same level of exposure to air pollution.

According to the authors, the study suggests that the role of diet is important in understanding environmental exposures, and that children can be protected from some of the harmful effects of indoor air pollution if they eat more and less foods rich in omega-3 fatty acids. Foods rich in omega-6 fatty acids.

the quote: Brigham EP, Wu H, McCormack M, Rice J, Kohler K, Vulcan T, Wu T, Coach A, Sharma S, Kollaghose F, Bose S, Hanson C, Romero K, Diet G, Hansel NN. 2019. Intake of omega-3 and omega-6 modifies asthma severity and response to indoor air pollution in children. Am J Respir Crit Care Med; doi: 10.1164/rccm.201808-1474OC [Online 29 March 2019].

The role of UHRF1 in colorectal cancer cell growth

A study funded in part by the NIEHS shows that blocking specific regions of a protein known as UHRF1 in human colon cancer cells turns on cancer-fighting genes and may impair colorectal cancer tumor growth. The researchers identified specific regions of UHRF1 that establish and maintain cancer-specific DNA methylation, which indicates molecular markers on DNA that can turn genes on or off.

Researchers have developed a way to block certain parts of the UHRF1 protein. They observed that two distinct parts of the protein helped cells maintain abnormal methylation patterns: the plant homeobox domain (PHD) segment and the SET segment and the RING-associated domain (SRA).

When the researchers blocked PHD and SRA passages by introducing mutations in the regions, hundreds of cancer-related genes were demethylated, impairing the ability of cancer cells to divide and migrate. Using mice implanted with human colon cancer cells, they found that blocking PHD and SRA or the function of the entire protein resulted in smaller tumors and less spread of cancer cells. In human colon cancer samples obtained from patients at the time of surgery, they elucidated UHRF1 expression and found an association between increased UHRF1 levels, increased promoter DNA methylation, worse prognosis and more aggressive tumor behavior.

According to the authors, in addition to offering a potential new way to control cancers, identifying these regions in UHRF1 may also help to better define colorectal cancer subtypes, improving clinicians’ ability to take a personalized approach to treatment.

the quote: Kong X, Chen J, Xie W, Brown SM, Cai Y, Wu K, Fan D, Nie Y, Yegnasubramanian S, Tiedemann RL, Tao Y, Chiu Yen RW, Topper MJ, Zahnow CA, Easwaran H, Rothbart SB, Xia L6, PILEN SP. 2019. Identification of UHRF1 domains that support maintenance of human colon cancer DNA methylation and oncogenic properties. Tumor Cell 35 (4): 633–648.

Manganese is associated with a hallmark of Parkinson’s disease

NIEHS grant recipients explored how exposure to manganese can lead to the accumulation and spread of an unfolded version of the protein alpha-synuclein, which is neurotoxic and a hallmark of Parkinson’s disease. The study provides new information about the biological processes linking exposure to manganese and the development of symptoms similar to Parkinson’s disease.

In a study using cells within the nervous system, researchers found that manganese disrupted alpha-synuclein formation and stimulated the packaging of these misfolded proteins into exosomes, small membrane-bound structures secreted by cells. This process provides a way for denatured proteins to travel from cell to cell to spread. They found that exosomes containing alpha-synuclein triggered an inflammatory response and led to neurotoxic effects.

Looking at the same process in mice, they found that manganese speeds up the transmission of faulty alpha-synuclein from one cell to another, resulting in neurodegenerative effects. They also analyzed serum samples from welders and found that welders exposed to manganese had increased false alpha-synuclein content in serum exosomes.

Although previous studies have shown links between alpha-synuclein misformation and manganese, this study provides new evidence for how manganese facilitates the development of neurodegenerative disease. According to the authors, analysis of serum exosomes may also provide a new method for detecting the presence of heterocyclic α-synuclein proteins, which may lead to early detection of Parkinson’s disease.

the quote: Harischandra DS, Rokad D, Neal ML, Ghaisas S, Manne S, Sarkar S, Panicker N, Zenitsky G, Jin H, Lewis M, Huang X, Anantharam V, Kanthasamy A, Kanthasamy AG. 2019. Manganese enhances the accumulation and exogenous prion-like translocation from cell to cell of alpha-synuclein. Si signal 12 (572).

(Sarah Amuligbe is a research and communications specialist for MDB Inc., a contractor with the Research and Training Outside the Walls of NIEHS.)

from San Jose News Bulletin https://sjnewsbulletin.com/environmental-factor-may-2019-leaves-of-the-month-outside-the-walls/