On Sept. 18, 2015, Stephen J. Elledge from Brigham and Women’s Hospital and Evelyn M. Witkin from Rutgers University received the Basic Medical Research Award for discoveries concerning the DNA-damage response a fundamental mechanism that protects the genomes of all living organisms.

Throughout their lives, cells withstand an onslaught of insults to their DNA. External agents such as chemicals and radiation bash it, and it also sustains abuse from within when normal physiological processes blunder. In humans, such events deliver tens of thousands of genetic wounds every day. The DNA-damage response detects not only DNA anomalies, but also other dangers, such as interruptions in the DNA-copying process. Living creatures then implement a multi-pronged strategy to ensure survival.

In the 1960s, Witkin began uniting these observations with others. First, she noticed parallels between two previously unrelated behaviors. In addition to evoking filamentous growth of bacteria, UV awakens bacterial viruses called phages, whose DNA has settled silently into the bacterial genome. Other investigators had just shown that UV irradiation initiates phage activation by destroying a protein that normally restrains its genes.

By that point, Witkin had discerned that UV treatment of her parent E. coli strain stimulates production of a substance that hinders cell separation. Perhaps, she speculated, manufacture of this substance normally is limited by an inhibitor (commonly called a repressor) that resembles the one that hampers phage gene activation. Maybe the same UV-induced molecular apparatus incapacitates both of the inhibitors, thus prompting filamentous growth and phage activation. This idea gained support from another group’s observation that cells with a single genetic defect spur both processes. A common pathway seemed to link the two phenomena.

In the meantime, Witkin had generated key insights into the mechanism by which UV light causes mutations. Radiation by itself does not generate inherited changes; subsequent cellular functions are required, she found. UV light triggers chemical reactions within DNA molecules that disrupt its structure and render the genetic code uninterpretable at those spots. Unless the original DNA letter is restored, she proposed, a promiscuous DNA-replication machine — an enzyme that is sloppier than the only one known at the time, which stops cold when it encounters DNA damage — inserts a random, and often incorrect, DNA building block. Witkin thus predicted accurately that DNA damage stirs production of an error-prone copying enzyme that fosters mutagenesis long before there was direct evidence for it.

Elledge’s illumination of the human pathway revealed in 2001 that ATR, a mammalian ATM-related kinase known to be essential for the DNA-damage response, requires another protein to do its job. The second protein, ATRIP, led him to the mechanism by which the pair senses DNA aberrations.