{"id":4526,"date":"2017-06-14T12:00:00","date_gmt":"2017-06-14T16:00:00","guid":{"rendered":"https:\/\/www.med.unc.edu\/biochem\/where-cigarette-smokings-damage-is-done-down-to-your-dna\/"},"modified":"2018-08-01T10:42:16","modified_gmt":"2018-08-01T14:42:16","slug":"where-cigarette-smokings-damage-is-done-down-to-your-dna","status":"publish","type":"post","link":"https:\/\/www.med.unc.edu\/biochem\/news\/where-cigarette-smokings-damage-is-done-down-to-your-dna\/","title":{"rendered":"Where Cigarette Smoking\u2019s Damage is Done . . . Down to Your DNA"},"content":{"rendered":"
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A new technique from UNC School of Medicine scientists led by Nobel Prize winner Aziz Sancar reveals the genome-wide DNA damage that a major carcinogen causes.<\/p>\n

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Aziz Sancar, MD, PhD (photo by Max Englund, UNC Health Care)
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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.<\/p>\n

The innovation comes from the laboratory of Nobel laureate Aziz Sancar, MD, PhD, the Sarah Graham Kenan Professor of Biochemistry and Biophysics at UNC\u2019s School of Medicine. In a study published in the Proceedings of the National Academy of Sciences<\/i>, 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 \u2013 benzo[\u03b1]pyrene.<\/p>\n

\u201cThis 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,\u201d said Sancar, who is also a member of the UNC Lineberger Comprehensive Cancer Center.<\/p>\n

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\u2019s 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.<\/p>\n

\u201cIt would be good if this helps raise awareness of how harmful smoking can be,\u201d he said. \u201cIt also would be helpful to drug developers if we knew exactly how DNA damage is repaired throughout the entire genome.\u201d<\/p>\n

BaP: Earth\u2019s Top Chemical Carcinogen?<\/b><\/p>\n

Benzo[\u03b1]pyrene (BaP) is a member of a family of simple, hardy, carbon-rich hydrocarbons \u2013 polycyclic aromatic hydrocarbons \u2013 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 \u2013 humans for example \u2013 BaP poses a serious environmental hazard. It\u2019s 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.<\/p>\n

\"Bap!<\/p>\n

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[\u03b1]pyrene diol epoxide (BPDE), which turns out to be worse than BaP itself.<\/p>\n

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\u2019t be duplicated properly during cell division. And if that happens, disease can be the result.<\/p>\n

\u201cIf a BPDE adduct occurs in a tumor suppressor gene and isn\u2019t repaired in a timely manner, it can lead to a permanent mutation that turns a cell cancerous,\u201d said Wentao Li, PhD, a postdoctoral researcher and lead author of the study.<\/p>\n

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.<\/p>\n

Repairs underway<\/b><\/p>\n

Sancar\u2019s new method<\/a> 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.<\/p>\n

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 section of DNA from another unaffected strand. This is possible because all cell-based life forms on Earth have two complementary strands of DNA. Meanwhile, the snipped-out damaged section of DNA floats free until garbage-disposal molecules eventually degrade it.<\/p>\n

Those free-floating bits of damaged DNA may be garbage to the cell, but they are solid gold for a scientist who wants to map all damage in a genome. With the new method, scientists can tag and collect these cast-off snippets, sequence them, and then fit together their sequences \u2013 like tiny pieces of a giant puzzle \u2013 to create a map of the genome. In the end, scientists have a complete map of the sites where repairs to damaged DNA have begun.<\/p>\n

Given the effort and expense required for DNA sequencing, the initial, proof-of-principle map published by Sancar, Li and colleagues doesn\u2019t have the highest resolution possible. But it points the way towards the routine scientific use of such maps, especially as costs drop, to better understand how DNA-damaging events lead to disease and death.<\/p>\n

This mapping technique should help answer several questions, such as:<\/p>\n