Dr Ruth Thompson
My research focuses on mechanisms of resistance to radiotherapy, specifically DNA damage sensing and repair. DNA damage is sensed and repaired in interphase and repair is largely repressed during mitosis due to the risk of telomere fusion. Whilst essential in normal cells, DDR can lead to radiation resistance in tumour cells. I have uncovered a novel DNA damage sensing a repair pathway in mitosis, immediately prior to cell division.
The spindle assembly checkpoint (SAC) is a mitotic checkpoint which detects correct chromosome alignment prior to cell division. I have observed marked mitotic arrest following treatment with ionizing radiation (IR) when earlier DNA damage checkpoints are removed using a Chk1 inhibitor indicating that there is also a checkpoint detecting DNA damage in mitosis . This arrest is dependent on the SAC effector BubR1 and is consistent with findings that mitotically-induced DNA Damage leads to mitotic arrest via the SAC. These findings along with my preliminary data, provide strong evidence of a hitherto unknown Mitotic DNA Damage Checkpoint (MDDC). This MDDC could lead to resistance to DNA Damaging agents even when combined with Chk1 inhibitors.
The main areas of research in my lab fall into three themes:
- Identification and characterisation of members of the MDDC
- Signaling pathways within the MDDC and crosstalk between this and other known checkpoints
- Exploiting this knowledge for the development of novel anticancer therapiesv
- Ando, K., Parsons, MJ., Shah, RB., Charendoff, CI., Paris, S., Liu, PH., Fassio, SR., Rohrman, BA., Thompson, R., Oberst, A et al. NPM1 directs PIDDosome-dependent caspase-2 activation in the nucleolus. J Cell Biol. 2017 Jun 5;216(6):1795-1810. PMID: 28432080
- Shah, R., Thompson, R., S. A mitosis-sensing caspase-activation platform? New insights into the PIDDosome. Mol Cell Oncol. 2015 Jul 6;3(3) PMID: 27314076
- Sarkurikar, N., Thompson, R., Montano, R., Eastman, A. Activation of CDK2 in S phase Determines the Differential Sensitivity of Human Cancer Cells to Chk1 Inhibition. Oncotarget. 2016 Jan 12 (2): 1380-94 PMID: 26595527.
- Thompson, R., Shah, R., Liu, P., Gupta, Y., Ando, K., Aggarwal, A., Sidi, S. An inhibitor of PIDDosome Formation. Molecular Cell. 2015 Jun 58 (5): 767-79 PMID:
- Montano, R., Thompson, R., Kaan, N., Hou, H., Chung, I., Eastman, A. Sensitization of human cancer cells to gemcitabine by the Chk1 inhibitor MK-8776: cell cycle perturbation and impact of administration schedule in vitro and in vivo. BMC Cancer. 2013 Dec 21 (13):604 PMID:
- Thompson, R., Eastman, A. The cancer therapeutic potential of Chk1 inhibitors: how mechanistic studies impact clinical trial design. Br J Clin Pharmacol. 2013 Sep;76(3):358-69 PMID:
- Thompson, R., Montano, R., Eastman, A. The Mre11 nuclease is critical for the sensitivity of cells to Chk1 inhibition. PLoS One. 2012 7 (8) e44021 PMID:
- Thompson, R., Meuth, M., Woll, P., Zhu, Y and Danson, S. Treatment with the Chk1 inhibitor Gö6976 enhances cisplatin cytotoxicity in SCLC cells. Int J. Oncol. 2012 40 (1): 194-202. PMID: 21894433.
- Gagou, ME., Ganesh, A., Thompson, R., Phear, G., Sanders, S. and Meuth, M. Suppression of apoptosis by PIF1 helicase in human tumor cells. Cancer Res. 2011 71 (14): 4998-5008 PMID: