Checkpoint activation in DNA damage response
Pol eta plays a crucial role in DNA repair. A DNA polymerase used by cells to replicate across compromised DNA, mutations in its gene increases the risk for xeroderma pigmentosum, a condition characterised by increased skin cancer. The TLSCHECK (Regulation of pol-eta by phosphorylation, ubiquitination and sumoylation) project has investigated pol eta, its function and regulation when it is modified by different proteins. The researchers focused on their roles during cell repair and DNA damage surveillance. Research has discovered a new protein that is required for recruitment of pol eta to the replication fork, where replication occurs. The need for this protein means that pol eta is not engaged if DNA replication is going smoothly and is important as the polymerase can introduce mutation if not tightly controlled. Another control mechanism for pol eta is phosphorylation and recent evidence shows that addition of phosphate occurs after DNA damage to activate the polymerase. The researchers identified new areas where this modification takes place. They are of the opinion that phosphorylation is another level of control of pol eta, when its application enables damage avoidance. Characterisation of molecular mechanisms of pol eta regulation has increased our understanding of how it contributes to genomic stability. New proteins identified could be the basis of development of diagnostic markers for atypical xeroderma pigmentosum. In the longer term, TLSCHECK research could well lead to novel cancer therapies based on cell death induction using synthetic lethality and drug combination strategies.
Keywords
DNA damage response, pol eta, polymerase, xeroderma pigmentosum, TLSCHECK
