Repair Mechanism of DNA Double-Strand Breaks
A team of Mayo Clinic researchers has uncovered a key step in the molecular pathway of repairing DNA double-strand breaks. The findings are published in the current edition of the journal Cell (www.cell.com).
Double-strand breaks in DNA can result from external agents such as ultraviolet (UV) radiation or mutagenic chemicals. If left unrepaired, a single DNA double-strand break can lead to cell death or cancer. As a consequence, cells have evolved elaborate machinery made of proteins that detect and repair these DNA lesions. A basic understanding of how this DNA repair machinery functions is important to finding ways of correcting the DNA double-strand break repair process when it goes awry. Studying DNA repair at the atomic level is necessary to understand the process.
The Mayo research team showed that 53BP1 - a human protein essential for repairing DNA double-strand breaks - is recruited to the sites of DNA damage by direct interaction with histone H4, a protein constituent of the DNA packaging structure called chromatin.
The team discovered that 53BP1 only recognizes one specific form of histone H4 in which two methyl groups are attached to a lysine amino acid (i.e. dimethylated histone H4). 53BP1 does not interact with histone H4 when the lysine has three methyl groups. To understand the origin of the high specificity of 53BP1 for dimethylated histone H4, the Mayo team deciphered the detailed atomic structure of 53BP1 in complex with histone H4 by using X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy.
It was known from previous studies in fission yeast that histone H4 and Crb2 (the protein counterpart of 53BP1 in fission yeast) are important components of the DNA repair machinery. "Our work shows that this also is true in humans and that direct binding of 53BP1 to histone H4 is necessary to bring 53BP1 near the damaged DNA. In a similar fashion, we also demonstrated that Crb2 directly interacts with histone H4," says Mayo Clinic structural biologist Georges Mer, Ph.D., who led the study.