Chemotherapy drugs damage DNA, keeping cells from replicating. However, according to researchers at the UNC School of Medicine and UNC Lineberger Comprehensive Cancer Center, the cells can repair the DNA, meaning that the drugs, including cisplatin and oxaliplatin, are not as effective as necessary.
As published in the journal Genes & Development and reported in Science Daily, these researchers "have developed a method for finding where this DNA repair happens throughout all of human DNA." This is "the first time scientists have been able to map the repair of DNA damage over the entire human genome," the article said.
The technique gives scientists a chance to locate and target the proteins cancer cells use to interfere with therapy, which could mean better cancer drugs that are more easily tolerated. Heading the research team is Aziz Sancar, MD, PhD, co-senior author, Sarah Graham Kenan Professor of Biochemistry and Biophysics and member of the UNC Lineberger Comprehensive Cancer Center.
According to Sancar, "Now we can say to a fellow scientist, 'tell us the gene you're interested in or any spot on the genome, and we'll tell you how it is repaired. Out of six billion base pairs, pick out a spot and we'll tell you how it is repaired."
While cells use many enzymes to repair damaged DNA, some proteins are more important than others. TFIIH is one that binds tightly, but extraction proven difficult until one of the researchers on the exposed the cells to ultraviolet radiation, used an antibody against the enzyme TFIIH to isolate the enzyme complex with the excised DNA damage and developed a way to extract the enzyme and the excised DNA fragment from the cells. After sequencing and computational analysis, the researchers could determine "where the DNA repair happened throughout the entire genome and thus generate a human genome repair map for the first time."
For details, please see University of North Carolina School of Medicine. "Researchers create DNA repair map of the entire human genome." ScienceDaily. ScienceDaily, 1 May 2015 (www.sciencedaily.com/releases/2015/05/150501103457.htm).
In a related story, researchers have determined that a protein that helps embryonic stem cells to retain their identity also promotes DNA repair, according to a study inThe Journal of Cell Biology and reported in Science Daily. The protein, Sall4, might have a similar role in cancer cells, enabling them to fix DNA damage to circumvent chemotherapy.
If embryonic stem cells can make these repairs, they can pass on mutations to their descendants. Researchers led by Yang Xu, from the University of California, San Diego, found that embryonic stem cells that lacked the protein Sall4, which suppresses differentiation of ESCs, could not mend double-strand breaks., a hazardous form of DNA damage in which both strands of the double helix are severed. They concluded that Sall4 could be considered a target for drug development in cancer biology.
For more details, see the story:The Rockefeller University Press. "Sall4 is required for dna repair in stem cells." ScienceDaily. ScienceDaily, 2 March 2015 (www.sciencedaily.com/releases/2015/03/150302104532.htm).