Dissecting the role of tubulin acetylation in DNA repair to improve response to PARPi
Lead Research Organisation:
Queen Mary University of London
Department Name: Barts Cancer Institute
Abstract
The maintenance of genomic information, encoded in the DNA of all cells, is key for all cells in our bodies to function. Our DNA is however exposed to damage, whether through its own replication or even exogenous sources such as sun's emitted ultraviolet radiation. DNA damage needs to be repaired to prevent harmful genetic changes and cell death. Thus, it is not surprising that to maintain the stability of our genetic material, cells have intricate systems that detect and repair these damages. There are two main pathways for repairing a specific type of DNA damage called double strand breaks (DSBs): non-homologous end joining (NHEJ) and homologous recombination (HR). While we know a lot about the components involved in these repair pathways, there's still a mystery surrounding something called DSB mobility. This refers to how these damaged sections of DNA move around inside the cell nucleus after an injury, which is important for repair. Previous studies support a role for the microtubules, thin filaments that provide intracellular tracks inside cells, in this process, although this is not well understood.
Recent work from our lab has shown that an abnormal increase in the number of centrosomes in a cell (a structure involved in cell division, cell motility), which happens in cancer, leads to changes in the composition of microtubules. These changes make it easier for certain components to move within the cell. Interestingly, when DNA damage occurs, microtubule composition also changes. This suggests that these changes could be the missing link between the DNA damage response and the movement of damaged DNA breaks. Indeed, our preliminary data supports this idea, showing that these changes in the microtubules are crucial for both the movement of damaged DNA and its repair. This discovery highlights the significance of microtubules in the DNA damage response. However, it's not all positive. Too much movement of the damaged DNA can have negative consequences, potentially leading to harmful changes in the DNA. This is particularly relevant in the context of a type of cancer treatment called PARP inhibitors that rely on the formation of deleterious chromosome fusions promoted by DNA mobility inside the nucleus. Understanding this could potentially improve the effectiveness of these inhibitors in treating cancer. It's important to note that while PARP inhibitors have shown promise in treating cancer, not all patients respond well, and most develop resistance. Therefore, finding ways to enhance their effectiveness is crucial for improving the survival rates of cancer patients. Our data suggest that understanding how microtubules influence DNA movement could lead to new strategies for improving the response to these inhibitors.
In this research proposal, our team will use their expertise in cell biology and imaging, along with specialized cancer model systems and tools, to tackle three main objectives: 1) Investigate how changes in the microtubules affects damaged DNA movement; 2) Understand why drives microtubule changes after DNA damage; and 3) Explore how microtubule changes can boost the response to PARP inhibitors in models of breast cancer.
Recent work from our lab has shown that an abnormal increase in the number of centrosomes in a cell (a structure involved in cell division, cell motility), which happens in cancer, leads to changes in the composition of microtubules. These changes make it easier for certain components to move within the cell. Interestingly, when DNA damage occurs, microtubule composition also changes. This suggests that these changes could be the missing link between the DNA damage response and the movement of damaged DNA breaks. Indeed, our preliminary data supports this idea, showing that these changes in the microtubules are crucial for both the movement of damaged DNA and its repair. This discovery highlights the significance of microtubules in the DNA damage response. However, it's not all positive. Too much movement of the damaged DNA can have negative consequences, potentially leading to harmful changes in the DNA. This is particularly relevant in the context of a type of cancer treatment called PARP inhibitors that rely on the formation of deleterious chromosome fusions promoted by DNA mobility inside the nucleus. Understanding this could potentially improve the effectiveness of these inhibitors in treating cancer. It's important to note that while PARP inhibitors have shown promise in treating cancer, not all patients respond well, and most develop resistance. Therefore, finding ways to enhance their effectiveness is crucial for improving the survival rates of cancer patients. Our data suggest that understanding how microtubules influence DNA movement could lead to new strategies for improving the response to these inhibitors.
In this research proposal, our team will use their expertise in cell biology and imaging, along with specialized cancer model systems and tools, to tackle three main objectives: 1) Investigate how changes in the microtubules affects damaged DNA movement; 2) Understand why drives microtubule changes after DNA damage; and 3) Explore how microtubule changes can boost the response to PARP inhibitors in models of breast cancer.
Technical Summary
Unrepaired DNA damage can lead to harmful genetic changes and cell death. To maintain the stability of our genetic material, cells have intricate systems that detect and repair these damages. There are two main pathways for repairing a specific type of DNA damage called double strand breaks (DSBs): non-homologous end joining (NHEJ) and homologous recombination (HR). While we know a lot about the components involved in these repair pathways, there's still a mystery surrounding something called DSB mobility. This refers to how these damaged sections of DNA move around inside the cell after an injury. Previous studies support a role for the microtubules, thin filaments that provide intracellular tracks important for transport inside cells, in this process, although this is not well understood.
Recent research from our lab has shown that an increase in the number of centrosomes in a cell (a structure involved in cell division) leads to changes in microtubules, in particular acetylation. These changes make it easier for certain components to move within the cell. Interestingly, after DNA damage occurs, microtubule acetylation also increases. This suggests that tubulin acetylation might be the key link between the DNA damage response and the movement of damaged DNA foci. Indeed, our preliminary data supports this idea, showing that microtubule acetylation is crucial for both the movement of damaged DNA and its repair. This discovery highlights the significance of tubulin acetylation and microtubules in the DNA damage response. However, it's not all positive. Too much movement of the damaged genetic material can have negative consequences, potentially leading to harmful changes in the DNA. This is particularly relevant in the context of a type of cancer treatment called PARP inhibitors that rely on the formation of damaging chromosome fusions promoted by DNA mobility inside the nucleus. Understanding this could potentially improve the effectiveness of these inhibitors in treating cancer. It's important to note that while PARP inhibitors have shown promise in treating cancer, not all patients respond well, and most develop resistance. Therefore, finding ways to enhance their effectiveness is crucial for improving the survival rates of cancer patients. Our data suggest that understanding how tubulin acetylation influences DNA movement could lead to new strategies for improving the response to these inhibitors.
In this research proposal, we will use their expertise in cell biology and imaging, along with specialized model systems and tools, to tackle three main objectives: 1) Investigate how acetylated tubulin affects damaged DNA movement; 2) Understand the mechanisms behind the increase in tubulin acetylation after DNA damage and its role in the DNA damage response; and 3) Explore how higher levels of tubulin acetylation can boost the response to PARP inhibitors.
Recent research from our lab has shown that an increase in the number of centrosomes in a cell (a structure involved in cell division) leads to changes in microtubules, in particular acetylation. These changes make it easier for certain components to move within the cell. Interestingly, after DNA damage occurs, microtubule acetylation also increases. This suggests that tubulin acetylation might be the key link between the DNA damage response and the movement of damaged DNA foci. Indeed, our preliminary data supports this idea, showing that microtubule acetylation is crucial for both the movement of damaged DNA and its repair. This discovery highlights the significance of tubulin acetylation and microtubules in the DNA damage response. However, it's not all positive. Too much movement of the damaged genetic material can have negative consequences, potentially leading to harmful changes in the DNA. This is particularly relevant in the context of a type of cancer treatment called PARP inhibitors that rely on the formation of damaging chromosome fusions promoted by DNA mobility inside the nucleus. Understanding this could potentially improve the effectiveness of these inhibitors in treating cancer. It's important to note that while PARP inhibitors have shown promise in treating cancer, not all patients respond well, and most develop resistance. Therefore, finding ways to enhance their effectiveness is crucial for improving the survival rates of cancer patients. Our data suggest that understanding how tubulin acetylation influences DNA movement could lead to new strategies for improving the response to these inhibitors.
In this research proposal, we will use their expertise in cell biology and imaging, along with specialized model systems and tools, to tackle three main objectives: 1) Investigate how acetylated tubulin affects damaged DNA movement; 2) Understand the mechanisms behind the increase in tubulin acetylation after DNA damage and its role in the DNA damage response; and 3) Explore how higher levels of tubulin acetylation can boost the response to PARP inhibitors.
People |
ORCID iD |
| Susana Godinho (Principal Investigator) |