Notorious Chemical May Pave the Way to New Gene Therapies
A notorious chemical is responsible for millions of deaths every year, and most people have never heard of it. Its savage effect on DNA results in 30% of all lung cancer deaths.
Ironically, its nefarious work leaves a signal that shows the way to new cancer and gene therapies.
The chemical is benzo[α]pyrene (BaP), an aromatic hydrocarbon found in space and in the smoke from a burning pile of leaves or a raging barbeque. But its deadliest effects occur when it is inhaled with cigarette smoke.
When BaP gets into the body, enzymes rush to break it down. The process releases benzo[α]pyrene diol epoxide (BPDE), which has catastrophic effects on DNA.
BPDE has a unique chemical ability. It binds with guanine, one of the four bases of DNA. BPDE binds so tightly that it physically gets in the way of any DNA action at this point on the strand. If the guanine-BPDE adduct is located at a key gene--say one for the repair of tumors or the timing of cell division--bad things can happen to the body.
BaP is such a powerful carcinogen that when it is applied to the skin of lab rats, the skin always produces tumors.
A group of scientists in the laboratory of Nobel Prize winner Aziz Sancar at the University of North Carolina's School of Medicine has taken BaP's devastating effects on DNA are using them to pioneer new pathways into cell repair. In an article in Proceedings of the National Academy of Sciences, lead author Wentao Li describes how the team used the adduct's own actions against itself.
When BPDE binds to guanine, a cell's DNA repair mechanisms go into action. They snip off the offending section of DNA, and then replace the missing segment so the strand returns to normal. The excised part of the DNA, with the bulky BPDE attached, floats around in the cell.
Sancar and his team located these snippets with the BPDE still attached, amplified those pieces, and sequenced them. They then had the ability to find where, at any place in the entire human genome, the vulnerable DNA segments exist.
Why are certain people more susceptible than other to lung cancer? What is it about their DNA sequences or their specific genes that render those area vulnerable to cigarette smoke? Sancar and Li have paved the way to answering these questions.
It is not the first time that Sancar and his lab have taken DNA damage and turned it on its head. Cells repair the DNA effects of UV light and the same procedures used in the BaP studies gave insights into how DNA is affected.
Will this breakthrough work lead to future gene therapies? We might be able to identity vulnerable DNA segments and replace them with ones that will not allow damaging adducts. All kinds of DNA damage might be avoided, and millions of lives might be saved every year.