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DNA Repair Pioneers Win Nobel

Larry H. Bernstein, MD, FCAP, Curator

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Tomas Lindahl, Paul Modrich, and Aziz Sancar have won this year’s Nobel Prize in Chemistry for their work elucidating mechanisms of DNA repair.

By Tracy Vence | October 7, 2015

http://www.the-scientist.com//?articles.view/articleNo/44182/title/DNA-Repair-Pioneers-Win-Nobel/

Tomas Lindahl, Paul Modrich, and Aziz Sancar today (October 7) took the 2015 Nobel Prize in Chemistry for their seminal research on DNA repair. The three scientists share equally in the prize “for having mapped, at a molecular level, how cells repair damaged DNA and safeguard the genetic information,” according to a Nobel Foundation statement.

“All living cells have repair mechanisms . . . to counter DNA damage,” Lindahl said during a Nobel Foundation press conference following the prize announcement. “[DNA damage] can result in a number of diseases, including cancer.” Asked about sharing in a Nobel Prize, he told reporters: “I feel very lucky and proud to be selected.”

Lindahl is a member of the Nobel Prize in Chemistry’s selection committee but did not participate in this year’s prize selection. He is a professor emeritus at the U.K.’s Francis Crick Institute. In the early 1970s, he was among the first to describe base excision repair, a process that works to patch decaying DNA throughout the cell cycle.

“Tomas was a kind of giant in the field and he has made really, really profound contributions to all aspects of DNA repair and DNA decay,” said Lindahl’s colleague Peter Karran of the Francis Crick Institute.

Later, Modrich, a professor of biochemistry and genomics at the Duke University Medical Center in Durham, North Carolina, described mismatch repair, which reduces the frequency of DNA replication-related errors. Sancar, a professor of biochemistry and biophysics at the University of North Carolina School of Medicine in Chapel Hill, described nucleotide excision repair, which cells use to counteract the effects of mutagens.

This year’s prize “is a very timely recognition of the field,” Karran said. “The field has made tremendous contributions to understanding how cancer develops, for example, and these people have made enormous contributions to understanding cancer, as well as to the basic science of DNA.”

Update (7:06 a.m.): Sancar “spent his entire career working in DNA repair,” Christopher Selby,  a research assistant professor at the University of North Carolina who has worked in Sancar’s lab since 1987, told The Scientist. “It’s exciting and interesting to see what it takes to get an award like that. . . . I’ve been fairly close with him throughout his career and I [have now] seen firsthand what goes into generating a body of work that goes into that sort of thing.”

Update (7:26 a.m.): “These guys have [made] tremendous, longstanding contributions to DNA repair, which is what keeps us all alive,” David Lilley, a professor of molecular biology at the University of Dundee, U.K., told The Scientist. “DNA is your library in the cell—you’ve gotta repair it, and it’s under massive onslaught. These [DNA repair] mechanisms are tremendously important.”

Update (7:34 a.m.): “I am absolutely thrilled. Paul was really there at the ground level. He really discovered these proteins in the DNA mismatch repair pathway,” said Lorena Beese, a professor of biochemistry at Duke University who has collaborated with Modrich since the mid-1990s. DNA repair “is such an essential area [of research],” Beese told The Scientist. “Mismatch repair, in particular—there are so many questions left on how this essential process works.”

GEN News Highlights

Oct 7, 2015

Nobel Prize in Chemistry Awarded to DNA Repair Researchers

Thomas Lindahl, Ph.D., Paul Modrich, Ph.D., and Aziz Sancar, M.D., Ph.D., have made fundamental contributions to the study of how cells repair DNA and maintain genomic integrity. [N. Elmehed. © Nobel Media 2015]

http://www.genengnews.com/media/images/GENHighlight/Oct7_2015_NElmehedNobelMedia2015_ChemistryNobelPrize3312717921.jpg

Recipients of the Nobel Prize in Chemistry were announced today acknowledging three scientists that  made fundamental contributions to the study of how cells repair DNA and maintain genomic integrity.

Each day our DNA is damaged by UV radiation, free radicals, and other carcinogenic substances. However, even without such external attacks, a DNA molecule within the cell is inherently unstable. Thousands of spontaneous changes to a cell’s genome occur on a daily basis and defects can arise when DNA is copied during cell division, a process that occurs several million times every day in the human body.

The reason our genetic material does not disintegrate into complete chemical chaos is that a host of molecular systems continuously monitor and repair DNA.Most cells use three main pathways to repair damage incurred to genetic material.

Thomas Lindahl, Ph.D., emeritus scientist at the Francis Crick Institute in London, was recognized for his discoveries in base excision repair—the pathway that constitutes the bulk of DNA restoration during the cell cycle from alkylation, methylation, and oxidative stress. In the early 1970s, many scientists believed that DNA was an extremely stable molecule, but Dr. Lindahl demonstrated that DNA decays at a rate that ought to have made the development of life on Earth impossible. This insight led him to discover the base excision repair mechanisms.

Paul Modrich, Ph.D., investigator at the Howard Hughes Medical Institute and professor of biochemistry Duke University School of Medicine, was honored for uncovering how cells resolve errors that occur during DNA replication. This so called mismatch repair pathway rectifies base-pairing errors within DNA and defects within this molecular machinery has been shown to increase genomic mutations up to 1,000-fold. Moreover, mismatch repair errors are the cause of the most common form of hereditary colon cancer (HNPCC) and are believed to contribute to the development of a subset of sporadic tumors that occur in a variety of tissues.

Aziz Sancar, M.D., Ph.D., professor of biochemistry and biophysics at the University of North Carolina School of Medicine, was acknowledged for his seminal work on the nucleotide excision repair pathway. Cells use this pathway to repair UV damage to DNA. Individuals born with defects in this repair system will develop skin cancer when exposed to sunlight. Additionally, the cell also utilizes nucleotide excision repair to correct defects caused by mutagenic substances and DNA lesions that create aberrant bulky regions within the helical strand.

These scientists have provided the essential insights into how cells function and maintain their genomic stability—knowledge that integral for the development of new cancer treatments.

Dr. Lindahl was one of my first influencers during research into glycosylases and DNA repair mechanisms. I still remember the academic debates occurring in hallways concerning the existence of the FAPY glycosylase. Very good to see Dr. Lindahl, Dr. Sancar (who contributed greatly) and Dr. Modrich being recognized for their lifelong works. I would wonder why Erol Friedberg was not mentioned though for his contributions to complement factors. However nice to see DNA repair recognized as a pivotal research area.