Nobel Recognizes Seminal Work in DNA Repair

Three scientists—Thomas Lindahl, PhD, Paul Modrich, PhD, and Aziz Sancar, MD, PhD—will share this year's Nobel Prize in Chemistry for pioneering research that established the inherent instability of DNA and the cellular mechanisms underlying its repair. Their work was critical to the development of conventional DNA-damaging cancer treatments and laid the foundation for newer therapies that inhibit repair pathways.

“Understanding these pathways provides us with the tools for identifying new anticancer drugs that can inhibit these repair mechanisms, and sensitize cancers to conventional chemotherapy and radiation,” says Alan D—Andrea, MD, director of the Center for DNA Damage and Repair at Harvard Medical School in Boston, MA. “That's helped in developing small-molecule inhibitors that interfere with cancer cells' ability to repair DNA damage and render them more sensitive to certain kinds of chemotherapy.”

As a case in point, the FDA last year approved olaparib (Lynparza; AstraZeneca), a PARP inhibitor that blocks the enzymes involved in base excision repair (BER), the pathway described by Lindahl. The drug was approved to treat advanced ovarian cancer associated with BRCA mutations.

BER is a process in which an altered base is removed by DNA glycosylases, followed by excision of the resulting sugar phosphate. The gap left in the DNA helix is filled in by the sequential action of DNA polymerase and DNA ligase. Lindahl, of the Francis Crick Institute and Clare Hall Laboratory in Hertfordshire, UK, identified a new family of DNA glycosylases and described their role in orchestrating BER.

Modrich, of the Howard Hughes Medical Institute and Duke University in Durham, NC, described mismatch repair, which corrects errors in DNA replication during cell division. Mismatches occur when an incorrect nucleotide is introduced during synthesis of a new DNA strand, resulting in formation of a non–Watson-Crick base pair that distorts the DNA. Defects in the mismatch repair genetic pathway have been found to cause hereditary nonpolyposis colon cancer.

Sancar, at the University of North Carolina, Chapel Hill, identified the enzymes involved in nucleotide excision repair (NER), which repairs DNA regions that contain chemical adducts, such as UV-induced thymine dimers that distort the DNA helix and interfere with replication and transcription. Mutations in the NER pathway are linked to a number of human genetic disorders, including xeroderma pigmentosum, characterized by hypersensitivity to UV radiation and a high risk for skin cancer.

Tomas Lindahl

Paul Modrich

Aziz Sancar

“These repair systems are very specialized and recognize particular types of damage,” says Stephen Elledge, PhD, a researcher in the Department of Genetics at Harvard Medical School in Boston, MA, who studies DNA damage repair. “You can draw an analogy with fixing potholes in roads: BER and NER find the problem, clear it out, and fill it in for repair, while mismatch repair acts as an editor that follows behind the polymerase to double-check its work and make sure it's right.”