DNA provides the body with an extremely intricate blueprint by which it functions, but how does it notice and correct itself when it is damaged or filled with errors?

Professor of Genetics at Harvard Medical School Stephen Elledge is working to answer that question. Last Thursday, he talked about his progress as the latest recipient of the 2012 Lewis S. Rosenstiel Award for Distinguished Work in Basic Medical Science.

The Rosenstiel Award is given to recognize researchers whose work has made a significant impact in the field of basic science research by a panel of Boston-area scientists who are appointed by the director of the Rosenstiel Basic Sciences Research Center.

In an interview with the Justice, Elledge said he was "deeply honored" to receive the award.

"I looked at the list of previous awardees and it's a stellar group of scientists, and it's really an honor to be considered among them," he said.

Prof. Jim Haber (BIOL) opened the lecture by introducing Elledge as "one of the most creative inventors of technology that [researchers] all use."

Elledge himself then took over, presenting an overview of the work that led to his involvement in researching the DNA damage response.

Elledge had originally studied DNA damage and repair as a Ph.D. student at the Massachusetts Institute of Technology. "I decided after doing that and getting my Ph.D., the last thing in the world I wanted to do was work on DNA and repair," he joked at the event. "And so I went as far away from it as I possibly could."

Eventually, Elledge said that he found himself interested in working on gene targeting. In an interview with the Justice, Elledge explained that he had located a gene in E. coli that coded for RecA, a protein involved in genetic recombination, the process by which new genetic information is produced by the crossing over of segments between alleles or homologous chromosomes.

Elledge intended to locate and clone the equivalent of the gene in yeast cells, and eventually in mammals.

"I thought genome engineering would be a great thing to study and I would just see where that would take me from there," he said.

However, Elledge discovered that the yeast gene he cloned did not code for RecA, but rather for ribonucleotide reductase, a protein important in the synthesis of deoxyribonucleotides, the building blocks of DNA.

"Of course, I found this to be incredibly depressing because I didn't want to work on nucleotide synthesis," said Elledge. "That wasn't the goal."

However, Elledge said that he noticed the RNA of the gene was activated in response to ultraviolet light, which causes mutations in DNA and agents that block DNA replication.

This observation led Elledge to the idea that there must be a large response that transmits information about these errors to these genes. This pathway, according to Elledge, is referred to as the DNA damage response.

Elledge said that each person's DNA undergoes tens of thousands of "events" or modifications each day, providing plenty of opportunities for mistakes to occur. The cell must be equipped to respond to these errors, either by correcting them if possible or by killing off the cell in order to prevent it from dividing and amplifying the damage.

According to Elledge, the response to this damage is more adaptive than innate, meaning that the cell must be able to transmit information about the type of damage in order to generate a specified response rather than having one general response for all types of damage.

In short, Elledge said that sensors circulating the DNA pick up information regarding the DNA damage and send the information to a control center in the cell, much like the brain. Here, information about the error is processed and a response is activated.

The response, said Elledge, must be highly specific, as many enzymes that can be activated by the response can also be destructive to the gene itself if turned on at the wrong time or place.

Elledge went on to summarize his work, focusing on two specific proteins that are involved in some pathways of the DNA damage response, SMARCAL1 and ZRANB3.

According to Elledge, both of these proteins seem to be related to each other, as parts of their DNA sequences are similar. They also share common functions. Both SMARCAL1 and ZRANB3 appear to be involved in restarting one of the steps of DNA replication.

Elledge's work also showed that SMARCAL1 is required for resistance to DNA damage and that ZRANB3 is necessary for the cell to survive after its DNA has been damaged during replication.

Elledge said in the interview that he hopes his work will provide the scientific community with a "different way of looking at how cells recognize and utilize" information about damage to DNA when they attempt to correct the genetic information affected.