The images of the DNA-repair protein Ku were published in the August 9, 2001, issue of Nature by Howard Hughes Medical Institute investigator Jonathan Goldberg and colleagues John R. Walker and Richard A. Corpina at Memorial Sloan-Kettering Cancer Center. Breaks in double-stranded DNA can occur randomly as a result of exposure to ionizing radiation or as programmed events during the gene shuffling that is necessary to create infection-fighting lymphocytes. The Ku heterodimer, consisting of two subunits, Ku70 and Ku80, is a member of a family of DNA repair proteins that fixes damaged DNA in order to preserve the integrity of the genome. When Ku encounters damaged DNA, it initiates a repair process, called non-homologous end joining (NHEJ), which stitches double-stranded broken ends back together even though the ends of each DNA strand may not be complementary.
Kus role in maintaining the integrity of the genome was established by earlier studies in which HHMI investigator Frederick W. Alt and his colleagues knocked out Ku70 and other NHEJ components and found that DNA repair was compromised and that aberrant rearrangements of chromosomes occurred with high frequency. Although these studies reinforced the role of Ku in DNA repair, the details of how Ku senses and initiates repair were still sketchy. The biochemistry is very clear, Goldberg said. Ku is sitting in the nucleus ready to sense DNA damage and to bind to DNA ends.
What remained unclear, however, was how Ku was able to distinguish between broken ends and intact DNA with such precision. Also, stitching DNA back together sounds dangerous because of the likelihood of losing genetic information, he said.
Contact: Jim Keeley
Howard Hughes Medical Institute