Understanding and sensing DNA damage

1998

Challenge

The ability of cells to sense and respond to DNA damage is crucial to their survival. Since damaged DNA is a known cause of cancer, determining how cells repair such damage is critical to understanding how the disease develops and finding new ways to prevent and treat it.

Advance

IRP investigator William Bonner, Ph.D., discovered a universal hallmark of DNA damage. He identified two specialized variants in a family of proteins associated with DNA, known as the histone H2A family, and discovered that breaks in the double-helix structure of DNA induce chemical modifications to one of these variants, called gamma-H2AX. Dr. Bonner also showed that gamma-H2AX molecules can easily be detected under a microscope when they are labeled with a fluorescent tag, which led to the development of a gamma-H2AX-based tool for measuring exposure to DNA-damaging radiation.

Impact

Dr. Bonner’s discoveries changed the way DNA repair is studied. For the first time, it was possible to study the dynamics of this type of DNA repair inside cells. In addition, the gamma-H2AX test has been used to determine how much radiation patients are exposed to during clinical procedures and could have value for assessing the effects of environmental radiation exposures. Now, researchers are exploring whether gamma-H2AX can be used to determine individual patients’ sensitivity to radiation, which would enable more personalized cancer treatments.

Publications

Bonner WM, Redon CE, Dickey JS, Nakamura AJ, Sedelnikova OA, Solier S, Pommier Y. (2008). GammaH2AX and cancer. Nat Rev Cancer. 8(12):957-67.

Paull TT, Rogakou EP, Yamazaki V, Kirchgessner CU, Gellert M, Bonner WM. (2000). A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage. Curr Biol. 10(15):886-95.

Rogakou EP, Boon C, Redon C, Bonner WM. (1999). Megabase chromatin domains involved in DNA double-strand breaks in vivo. J Cell Biol. 146(5):905-16.

Rogakou EP, Pilch DR, Orr AH, Ivanova VS, Bonner WM. (1998). DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem. 273(10):5858-68.

Bonner WM, West MH, Stedman JD. (1980). Two-dimensional gel analysis of histones in acid extracts of nuclei, cells, and tissues. Eur J Biochem. 109(1):17-23.

West MH, Bonner WM. (1980). Histone 2A, a heteromorphous family of eight protein species. Biochemistry. 19(14):3238-45.