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How cigarette smoking damage is done

Now, for the first time, University of North Carolina (UNC) School of Medicine has created a map of how and where DNA damage occurs...


The innovation comes from the laboratory of Nobel laureate Aziz Sancar MD, PhD, the Sarah Graham Kenan Professor of Biochemistry and Biophysics at UNC's School of Medicine. In a study published in the Proceedings of the National Academy of Sciences, Sancar and his team developed a technique for mapping sites on the genome that are undergoing repair following a common type of DNA damage. They then used that technique to map all damage caused by the major chemical carcinogen - benzo[a]pyrene.

Explains Sancar:"This is a carcinogen [benzo[a]pyrene] that accounts for about 30 percent of the cancer deaths in the United States, and we now have a genome-wide map of the damage it causes."

Such maps will help scientists better understand how smoking-induced cancers originate and why some people are more vulnerable or resistant to cancers, as well as how these cancers might be prevented. Sancar hopes providing such stark and specific evidence of smoking's harm at the cellular level might induce smokers to kick their habit. There are about 40 million smokers in the United States and a billion worldwide.

"It would be good if this helps raise awareness of how harmful smoking can be," he said. "It also would be helpful to drug developers if we knew exactly how DNA damage is repaired throughout the entire genome."

Benzo[a]pyrene (BaP) is a member of a family of simple, hardy, carbon-rich hydrocarbons - polycyclic aromatic hydrocarbons - that can form even in outer space. Scientists think these molecules might have seeded simple carbon-based life on Earth and other planets. But for more evolved and complex DNA-based life forms - humans for example - BaP poses a serious environmental hazard. It's a byproduct of burning organic compounds, such as tobacco plants.
Everyday forms of combustion, from forest fires to diesel engines and barbecue grills, put a lot of BaP into our air, soil, and food. But nothing in ordinary life delivers it into human tissue more efficiently than puffing on a lit cigarette.

Typically, when a toxic hydrocarbon gets into a person through breathing or eating, there are enzymes in our blood to break it down into smaller, safer molecules. That happens for BaP, too, but the protective reactions also yield a compound called benzo[a]pyrene diol epoxide (BPDE), which is much worse than BaP itself.

BPDE reacts chemically with DNA, forming a very tight bond at the guanine base on the DNA ladder. This new bond means that genes can no longer make proper proteins and DNA can't be duplicated properly during cell division. When this happens, disease can be the result.

"If a BPDE additon occurs in a tumor suppressor gene and isn't repaired in a timely manner, it can lead to a permanent mutation that turns a cell cancerous," explains Wentao Li PhD, a postdoctoral researcher and lead author of the study.

There is no doubt about the cancer causing ability of this compound. Paint a moderate dose of BaP on the skin of a lab mouse and tumors almost certainly erupt. BaP, via BPDE, has long been recognized as a promoter of multiple types of cancer and is considered the single most important cause of lung cancer.
Sancar's new method for mapping BaP-induced DNA damage enables scientists to identify the sites on the genome where cells are trying to repair such damage. Sancar won a share of the 2015 Nobel Prize for Chemistry for teasing apart the detailed workings of this biochemical repair process.

The process is known as nucleotide excision repair, it involves recruiting special proteins that perform DNA surgery. They snip out the affected strand of DNA, and then DNA-synthesizing enzymes reconstruct that missing section from DNA of an unaffected strand. This is possible because all cell-based life has two complementary strands of DNA. The damaged and snipped-out section of DNA then floats free until degraded by garbage-disposal molecules.
Such free-floating bits of damaged DNA may be garbage to a cell, but are now solid gold to a scientist who wants to map all genome damage. With nucleotide excision repair, scientists can tag and collect these cast-off snips of DNA, sequence them and then fit them back together - like tiny pieces of a giant puzzle - to create a map of the genome. In the end of this process, scientists have a complete map of sites on the genome where repairs to damaged DNA have started.

This mapping technique should help answer several questions, such as:

Dose of toxin needed to overwhelm average nucleotide excision repair capacity?

Variations in which genes give people more or less capacity to repair DNA damage?

Are there spots on the genome where repairs are inherently less likely to occur?

Repairs of BPDE damage tend to happen more often when BPDE-burdened guanine (G) is next to a cytosine (C) rather than a thymine (T) or adenine (A) on the DNA ladder. This suggests there are "hotspots" of higher risk for BPDE-induced mutation.

Sancar, Li, and their colleagues are using their new technique to map DNA damage repair associated with other environmental toxins. Their next project focuses on aflatoxins, a family of mold-produced molecules often found in poorly stored nuts and grains. These toxins damage DNA and are major causes of liver cancer in developing countries.

Sancar: "I'm certain that all this information will lead to a better understanding of why certain people are predisposed to cancer, and which smoking-related mutations lead specifically to lung cancer."

Significance
Benzo[a]pyrene (BaP) is a widespread potent carcinogen found in food, coal tar, cigarette smoke, and industrial smoke. Cigarette smoking is the leading cause of lung cancer, and the mutagenesis in smoking-associated lung cancer is determined by multiple factors, including nucleotide excision repair. We have developed a general method for genome-wide mapping of nucleotide excision repair at single-nucleotide resolution and applied it to generate repair maps of UV- and BaP-induced DNA damage in human. Results show a novel sequence specificity of BaP diol epoxide-deoxyguanosine repair. This general method can be used to study repair of all types of DNA damages that undergo nucleotide excision repair.

Abstract
Benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon, is the major cause of lung cancer. BaP forms covalent DNA adducts after metabolic activation and induces mutations. We have developed a method for capturing oligonucleotides carrying bulky base adducts, including UV-induced cyclobutane pyrimidine dimers (CPDs) and BaP diol epoxide-deoxyguanosine (BPDE-dG), which are removed from the genome by nucleotide excision repair. The isolated oligonucleotides are ligated to adaptors, and after damage-specific immunoprecipitation, the adaptor-ligated oligonucleotides are converted to dsDNA with an appropriate translesion DNA synthesis (TLS) polymerase, followed by PCR amplification and next-generation sequencing (NGS) to generate genome-wide repair maps. We have termed this method translesion excision repair-sequencing (tXR-seq). In contrast to our previously described XR-seq method, tXR-seq does not depend on repair/removal of the damage in the excised oligonucleotides, and thus it is applicable to essentially all DNA damages processed by nucleotide excision repair. Here we present the excision repair maps for CPDs and BPDE-dG adducts generated by tXR-Seq for the human genome. In addition, we report the sequence specificity of BPDE-dG excision repair using tXR-seq.


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Aug 8, 2017   Fetal Timeline   Maternal Timeline   News   News Archive




Scientists have known for decades that smoking cigarettes causes DNA damage, which leads to lung cancer. Now, for the first time, UNC School of Medicine scientists created a method for effectively mapping that DNA damage at high resolution across the genome. CREDIT Christ-claude Mowandza-ndinga (UNC Health Care)



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