Preserving salivary gland physiology against genotoxic damage - the Tousled way

Tousled and its homologs are evolutionarily conserved serine/threonine kinases present in plants and animals. Human Tousled-like kinases, TLK1 and TLK2, are implicated in chromatin assembly during DNA replication, chromosome segregation during mitosis, as well as in DNA damage response and repair. They share a high degree of sequence similarity, but have few non-redundant functions. Our laboratory has studied TLK1 and found that it increases the resistance of cells to ionizing radiation (IR) damage through expedited double-strand break (DSB) repair. DSBs are life-threatening lesions which when repaired restore DNA integrity and promote cell survival. A major focus in our laboratory is to dissect TLK1's role in DSB response and repair and study its usefulness in averting salivary gland hypofunction, a condition that invariably afflicts patients undergoing regional radiotherapy. The identification of anti-silencing factor 1 (ASF1), histone H3, and Rad9 as substrates of TLK1 links the protein to chromatin organization and DNA damage response and repair. However, recent findings of new interacting partners that include NEK1 suggest that TLK1 may play a broader role in DSB repair. This review provides a brief overview of the DNA damage response and DSB repair, and it highlights our current understanding of TLK1 in the process.