Nonhomologous end joining (NHEJ) repairs DNA double-strand breaks created by ionizing radiation and V(D)J recombination of the immunoglobulin genes. The breaks often leave mismatched or non-ligatable ends, and NHEJ must repair the breaks with high efficiency and minimal nucleotide loss.

Our lab developed a reconstituted system to study DNA end joining using purified proteins. We discovered a mismatched end (MEnd) ligase activity requiring the core NHEJ proteins, Ku, XRCC4, Ligase IV and Cernunnos/XLF (Tsai et al., 2007). Remarkably, MEnd ligase overcomes mismatched bases in 3'-overhangs to join the ends with high efficiency. By ligating ends refractory to all other ligases, MEnd ligase ensures efficient repair of broken chromosomes and maximum preservation of DNA sequence.

The focus of my research is to elucidate the molecular basis of ligation of mismatched ends.