Study sheds light on the repair of a type of DNA damage

A group of researchers from the USA and Spain has identified a protein involved in the repair of a type of DNA damage, called DNA-protein crosslinks (DPCs). The discovery provides clues to the repair pathway of DPCs.

A DPC is created when a protein is covalently bound to DNA. This type of DNA damage is induced by a variety of agents, including metals, aldehydes, radiation, and, particularly, chemotherapeutic drugs. If not properly repaired, DPCs accumulate and cause cell death. DPCs have both a good side and a bad side. On the one hand, the accumulation of DPCs is associated with mutagenesis and genomic instability and leads to various diseases like cancer. On the other hand, chemotherapeutic drugs induce the formation of DPCs to kill cancer cells.

Despite the important roles of DPCs in disease development and cancer treatment, many aspects of DPCs still remain unclear. To understand how a DPC is repaired, it is important to understand how it is created. Dr. Matthew Schellenberg from National Institute of Environmental Health Sciences (NIEHS), who is the first author of the new study, noted that when DNA in cells becomes tangled, the protein TOP2 helps untangle it.

TOP2 is an enzyme that controls topological states of DNA by transient breakage and subsequent rejoining of DNA strands. TOP2 is a target of several anticancer drugs and mutations in it correlate with drug resistance. A variety of endogenous and exogenous agents, such as chemotherapeutic drugs, disrupt the function of TOP2. As a result, TOP2 gets stuck on DNA, leading to the formation of a stable TOP2-DPC complex that can cause cell damage and death.

Another protein called TDP2 is known to enable the repair of TOP2-DPCs. However, the precise mechanisms remain elusive. Dr. Schellenberg and colleagues found that a protein, known as ZATT, cooperates with the TDP2 protein to resolve TOP2-DPCs. The activity of ZATT facilitates the recruitment of TDP2 to DPCs, so that TDP2 can repair DPCs.

In summary, the study identifies ZATT as a DNA repair factor that controls DPC repair. Since certain anticancer drugs induce DPCs to kill cancer cells, the findings may have implication in cancer treatment. The researchers have published their findings in the 14 Sep 2017 issue of the journal Science.
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