Where cigarette smoking's damage is done -- down to your DNA

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. 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 useful 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[α]pyrene. "This is a carcinogen 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," Sancar said. Maps like these will help scientists better understand how smoking-induced cancers originate, why some people are more vulnerable or resistant to cancers, and how these cancers might be prevented. Sancar also hopes that providing such stark and specific evidence of smoking's harm at the cellular level might induce some smokers to kick the 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." BaP: Earth's Top Chemical Carcinogen? Benzo[α]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, enzymes in our blood break it down into smaller, safer molecules. That happens for BaP, too, but the protective reactions also yield a compound called benzo[α]pyrene diol epoxide (BPDE), which turns out to be worse than BaP itself. BPDE reacts chemically with DNA, forming a very tight bond at the nucleobase guanine. This bond, or adduct, means that the genes can no longer make proper proteins and DNA can't be duplicated properly during cell division. And if that happens, disease can be the result. "If a BPDE adduct 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," said Wentao Li, PhD, a postdoctoral researcher and lead author of the study. There is no doubt about the basic carcinogenicity of chemical reaction. Paint a moderate dose of BaP on the skin of a lab mouse, and tumors are almost certain to 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. Repairs underway 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 the damage. Sancar won a share of the 2015 Nobel Prize for Chemistry for teasing apart the detailed workings of this biochemical repair process. Known as nucleotide excision repair, it involves the recruitment of special proteins that perform DNA surgery. They snip out the affected strand of DNA. If all goes well, DNA-synthesizing enzymes then reconstruct the missing sec.