Papers of the Month
By Sara Amolegbe
DNA polymerase theta protects against UV-induced cancer
NIEHS grantees provided evidence that the enzyme DNA polymerase theta (pol Q) protects against skin cancer induced by ultraviolet (UV) light, although pol Q also increases the number of UV-induced mutations. They observed that pol Q might play a protective role through a process called error-prone translesion synthesis (TLS), which allows DNA to replicate past mutations and tolerate DNA damage.
To understand the role of TLS in skin cancer formation, the researchers used cell studies to analyze the enzymes that synthesize DNA molecules, known as DNA polymerases, to determine which DNA polymerase is responsible for generating UV-induced mutations. In cell studies, they showed that pol Q led to an increase in mutations induced by UV exposure and was required to generate certain types of mutations.
Because pol Q led to DNA mutations in cells, the scientists generated a pol Q-deficient mouse model and examined susceptibility to UV-induced skin cancers. Contrary to expectations, the team found that pol Q-deficient mice were more susceptible to skin cancer from UV damage.
The team analyzed the replication of UV-damaged DNA in the mice and discovered that TLS mechanisms by pol Q and other polymerases prevented the collapse of replication forks. Replication forks are active areas of DNA replication that can collapse at sites of DNA damage. This can lead to genomic instability and promote tumor development. Because TLS by pol Q prevented replication fork collapse, the authors suggested that although pol Q can induce mutations, it also provides a safeguard against cancer formation.
Citation: Yoon JH, McArthur MJ, Park J, Basu D, Wakamiya M, Prakash L, Prakash S. 2019. Error-prone replication through UV lesions by DNA polymerase theta protects against skin cancers. Cell 176(6):1295–1309.e15.
Omega-3 and omega-6 may play opposite roles in asthma
An NIEHS-funded study found that children with more dietary omega-3 fatty acids, present in foods such as salmon, had less severe asthma and fewer symptoms triggered by indoor air pollution. The same study showed an opposite effect for high levels of dietary omega-6 fatty acids, found in corn oil and other foods, which were linked to more severe asthma and more symptoms.
The researchers studied 135 children with asthma in Baltimore. Asthma severity and lung function were assessed at the beginning of the study, at three months, and at six months. At each time point, the researchers captured week-long average home indoor concentrations of air particulate matter, dietary intake of omega-3 and omega-6 fatty acids, and information on daily asthma symptoms and inhaler use.
The researchers found that for each additional gram of omega-6 in their reported diet, 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, researchers saw 3-4% lower odds of daytime asthma symptoms. Overall, children who ate more omega-3 were less likely to have symptoms even at the same level of air pollution exposure.
According to the authors, the study suggests that the role of diet is important in understanding environmental exposures, and that children may be protected from some of the harmful effects of indoor air pollution if they eat more foods rich in omega-3 fatty acids and less foods rich in omega-6 fatty acids.
Citation: Brigham EP, Woo H, McCormack M, Rice J, Koehler K, Vulcain T, Wu T, Koch A, Sharma S, Kolahdooz F, Bose S, Hanson C, Romero K, Diette G, Hansel NN. 2019. Omega-3 and omega-6 intake 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].
Role of UHRF1 in colorectal cancer cell growth
Blocking specific regions of a protein known as UHRF1 in human colon cancer cells switches on cancer-fighting genes and may impair colorectal cancer tumor growth, according to a study funded in part by NIEHS. The researchers defined specific regions of UHRF1 that establish and maintain cancer-specific DNA methylation, which refers to molecular tags on DNA that can switch genes on or off.
The researchers developed a way to block certain parts of the UHRF1 protein. They observed that two distinct segments of the protein helped the cells maintain abnormal methylation patterns: the plant homeodomain (PHD) segment and the SET and RING-associated domain (SRA) segment.
When the researchers blocked the PHD and SRA segments by inserting mutations into the regions, hundreds of cancer-associated genes became demethylated, impairing the ability of the 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 led to smaller tumors and less spread of cancer cells. In human samples of colon cancers obtained from patients at the time of surgery, they profiled expression of UHRF1 and found an association between increased UHRF1 levels, increased promoter DNA methylation, and worse prognosis and more aggressive tumor behavior.
According to the authors, in addition to offering a potential new way to control cancers, identification of these regions on UHRF1 may also help better identify colorectal cancer subtypes, improving physicians’ ability to take a personalized approach to treatment.
Citation: 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, Baylin SB. 2019. Defining UHRF1 domains that support maintenance of human colon cancer DNA methylation and oncogenic properties. Cancer Cell 35(4):633–648.e7.
Manganese linked to hallmark of Parkinson’s disease
NIEHS grantees discovered how manganese exposure can lead to aggregation and spread of a misfolded version of the alpha-synuclein protein, which is toxic to nerve cells and a hallmark of Parkinson’s disease. The study provides new information about the biological processes that link manganese exposure and the onset of Parkinson’s-like symptoms.
In a study using cells found within the nervous system, the researchers found that manganese induced alpha-synuclein misfolding and stimulated the packaging of these misfolded proteins into exosomes, which are small membrane-bound structures secreted by cells. This process provides a way for the misfolded proteins to transfer from cell to cell to propagate. They found that the exosomes containing alpha-synuclein mounted an inflammatory response and led to neurotoxic effects.
Looking at the same process in mice, they found that manganese accelerated the cell-to-cell transmission of misfolded alpha-synuclein, which resulted in neurodegenerative effects. They also analyzed blood serum samples from welders and found that welders exposed to manganese had increased misfolded alpha-synuclein content in their serum exosomes.
Although previous studies have shown links between alpha-synuclein misfolding and manganese, this study provides new evidence for how manganese facilitates progression of neurological disease. According to the authors, the analysis of serum exosomes may also provide a new way to detect the presence of misfolded alpha-synuclein proteins, which could lead to earlier detection of Parkinson’s disease.
Citation: 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 promotes the aggregation and prion-like cell-to-cell exosomal transmission of alpha-synuclein. Sci Signal 12(572).