Bo Stenerlöw's projects on radiation biology and DNA repair

DNA double-strand breaks (DSBs) in the chromosomal DNA are potentially lethal for the cell. The cellular repair capacity is the major parameter affecting cell survival after exposure to ionizing radiation, and incorrectly repaired or unrepaired DSBs might lead to chromosomal aberrations that are lethal for the cell. The overall aim of our research is to provide novel knowledge about cellular processes that have the potential to increase the efficacy of radiation treatment of tumours.

Cancer therapy with ionizing radiation is lethal to tumour cells because induced DNA double-strand breaks (DSBs) are not correctly repaired. The last decades, research on DNA repair has led to many novel insights in cellular repair but several important aspects of radiation-induced DSB are still unresolved.

For instance, it is still unclear how primary damage is detected, how this initiates signal transduction and activates DNA repair proteins, selection of repair pathway and how DNA repair mechanisms are affected by radiation quality (i.e. clustered damaged DNA sites generated by high LET radiation). As we gain a better understanding of DSB repair mechanisms and the regulation of pathway choice, it is likely that basic mechanistic insights will translate into clinical benefits.
 

Repair pathways and signaling

The main repair pathway of radiation-induced DSBs is non-homologous end-joining (NHEJ). The rapid binding of broken DNA ends is a key event in repair of DSB and cells defective in NHEJ are extremely sensitive to ionizing radiation. The function of this initial step and the following protein interactions may largely affect the outcome of repair. Although the major protein complexes involved in NHEJ have been identified, it is still not fully understood how, when and where the major protein complexes come together and repair DSB.

We are currently investigating how NHEJ proteins interact and how they may regulate other repair pathways and cellular processes.
 

Clustered damaged sites in DNA

Recent and planned radiation therapy modalities use high-LET (LET: linear energy transfer) radiation, in terms of accelerated ions or radioactive nuclides emitting a-particles or Auger-electrons in order to effectively treat malignant tumours: a relatively low dose of high-LET radiation has a high cell killing efficiency. However, the number generated DSB is similar to that induced by conventional gamma radiation and this strongly implicate that DSB is a highly heterogeneous type of DNA damage: the dense deposition of energy from high-LET radiation results in both complex DSBs (i.e. DSBs associated with additional DSBs, SSBs or base lesions within 20-30 bp) and clustered DNA breaks within 1-2 Mbp of chromatin.

It is evident that clustered lesions are much more difficult to restore, but there is no information about failure in specific steps in the repair process. Our research is focused on DNA damage localization within chromatin and the mechanisms involved in DNA damage recognition at clustered damaged sites.
 

Sensitizing tumour cells

New knowledge about DNA repair mechanisms and how these are affected by radiation quality and targeting of growth factor receptors commonly overexpressed in tumour cells, have the potential to further increase the efficacy of radiation treatment of tumours. Importantly, even a relatively small modification of the radiation response in the tumour cell population may have a significant impact on the probability to kill all clonogenic tumour cells over several weeks of IR fractionation or radionuclide exposure.

Several drugs are known to sensitize cells to IR and considering the potential lethal induction of DNA double-strand breaks, drugs that interfere with the repair of these breaks are obvious candidates. In recent years, there has been rapid progress in the identification of new molecular targets that could be useful for cancer therapies. Some of these promising targets are members of the heat shock protein (HSP) family, which is a group of proteins that are induced in response to cellular stress.

We here investigate novel HSP90 inhibitors by characterizing their cellular and molecular effects, and their effects on cells and tumours in combination with IR.