For UNC-Chapel Hill biochemistry professor Aziz Sancar and the members of his lab, there’s no resting on the laurels of the Nobel Prize in chemistry that Sancar shared in the fall of 2015 for his life’s work in figuring out one of the key mechanisms of DNA repair.
Sancar and several of his post-docs just rolled out two new papers, both published in the Proceedings of the National Academy of Sciences, that report success in their attempts to come up with a better set of tools for mapping both the repairs the DNA molecule makes to itself after being exposed to known carcinogens, and the actual damage it’s suffered.
Neither age — Sancar will turn 71 in about three months — nor the fuss over the Nobel are slowing down the professor’s work.
“He just wants to focus on the science,” said Wentao Li, the post-doc who was the lead author of one of the papers, which reported on how well a newly refined mapping technique worked in spotting repairs triggered by exposure to a chemical in cigarette smoke that’s known to be the major cause of lung cancer.
The other paper, worked on by a portion of the same team, this time with post-doc Jinchuan Hu as the lead author, used another mapping refinement to look at DNA damaged from being exposed to ultraviolet light, the cause of skin cancer.
There, Hu, Sancar and two of their colleagues said they’d found that while UV-induced damage seemed evenly distributed in the genome, the ensuing DNA repairs weren’t. But they said the mapping itself, when combined with earlier methods, “makes it possible to measure damage and repair independently and simultaneously at unprecedented sensitivity,” for use in understanding how the changes to the molecule trigger cancer.
The ultimate objective is to use the expanded toolbox to “answer fundamental questions about how mutations are formed,” and about the proteins that help the repair process along in the DNA molecule, said Sheera Adar, a former Sancar lab post-doc who contributed to the data-analysis work that went into both of the papers.
The post-docs, and Sancar, are about 20 months removed from the October day where they learned he would share the 2015 Nobel in chemistry with Duke University professor Paul Modrich and British researcher Tomas Lindahl. Each of the winners had pinned down a distinctly different mechanism of DNA repair, which is key to the existence of life given that without it, the DNA molecule would quickly break down.
That day, UNC-CH officials gave Li, Wu, Adar and fellow post-doc Yi-Ying Chiou literal front row seats at the campus celebration of the announcement, and their mentor and boss made a point of thanking them for their work. Chiou was another co-author on the Li-led paper and like Adar, contributed data-analysis work to it.
Sancar’s specialty is the workings of “nucleotide excision repair,” the process that see proteins chop out damaged portions of one DNA strand and use the undamaged analogue in the molecule’s other strand as models for their replacement. The damaged bits have turned out to be key to the ability to map repairs, as researcher can also compare them to the undamaged molecule to see where they come from.
For the paper Li led, the lab sought to improve a mapping process that relied on first doing some repairs to the damaged bits so they could go through gene sequencing. That, the team said “has limitations” because a lot of the damage can’t actually be reversed. The solution involves a workaround that’s both “simpler and more versatile,” they say.
Li, Sancar and their colleagues tested it by mapping repairs to the DNA molecule triggered by its exposure to benzo[a]pyrene, a byproduct of burning organic compounds like tobacco. They were able to see where it tended to bond to the strand, and believe that as sequencing technology advances, it’ll be possible to figure out whether mutations there are sparking lung cancer.
Moreover, the new mapping technique “can be used for all kinds of damage that can be repaired by excision repair,” Li said, listing some types of skin and liver cancers as candidates for similar reconnaissance and adding that it also might be useful in seeing how chemotherapy drugs attack cancers.
Adar — who’s now in the midst of setting up her own lab at the Hebrew University of Jerusalem — said Sancar has created “a very collaborative environment” in his group at UNC-CH and as it happens, “a very international one” too. The papers’ co-authors come from China, Israel and, in the case of Sancar and post-doc Ogun Adebali, Turkey.
“He is going strong,” she said of Sancar. “We say in Hebrew that when you’re really passionate about something, it’s burning inside you. Aziz lives and breaths science. He needs to know this.”