Dr Qian Wu
DNA double-strand breaks (DSBs) and Interstrand crosslinks (ICLs) are highly toxic DNA lesions for cells. Ionizing radiation (IR) from radiotherapy and chemical crosslinking agents from chemotherapy generate large amount of DSBs and ICLs in order to kill cancer cells, which are under high replication stress. Radiotherapy or chemotherapy treats around a third of cancer patients in the UK each year. DNA damage response (DDR) and repair play critical roles in influencing the efficiency and sensitivity of these cancer treatments. At the same time, the differences between DDR and repair function in normal vs. tumour cells allowed the creation of a new class of targeted anti-cancer drugs called PARP (poly ADP ribose polymerase) inhibitor (PARPi) through a principle called synthetic lethality. However, intrinsic or acquired resistance to these drugs occurs in many patients causing a lack of response or tumour regrowth. We therefore aim to understand the basic mechanisms of DNA repair that underpin disease outcomes by combining structure determination, protein tool development and in vitro/cellular characterisation.
Current major projects
- Understanding and Controlling DNA repair pathway choice for double-strand breaks
- Defining the structural mechanism of the cellular response to DNA interstrand crosslink lesions
Detailed research programme
Non-homologous end joining (NHEJ) and homologous recombination (HR) are the two major pathways for repairing DSBs, which differ in their accuracy and speed. The condition of the DNA ends is a key factor that regulates the pathway choice between NHEJ and HR. The choice between DNA repair pathways has a direct effect on cancer treatments, especially for the therapeutic efficacy of PARPi in cancer patients with BRCA1/2 mutations. This project aims to help solve this problem by studying a newly discovered player in DDR: the Shieldin complex. Shieldin (SHLD1, SHLD2, SHLD3 and REV7) is part of the 53BP1 signalling that promotes NHEJ, and mutations in Shieldin alter the efficiency of cancer cells responding to PARPi and other anti-cancer drugs.
This project focuses on a structurally uncharacterised DDR protein complex called SLF1-SLF2 (SMC5/6 localization factor 1 and 2). This complex is recruited when DNA replication fork progression is blocked by ICLs. Knockdown of SLF1 or SLF2 levels in cells increases the number of chromosomal aberrations induced by the crosslinking and anti-cancer drug mitomycin C, suggesting that SLF1 and SLF2 are important for maintenance of genome stability. Why SLF1-SLF2 is essential for stabilising RAD18 and SMC5/6 together at the DNA damage site to mediate this protection against replication-associated genotoxic stress and sister chromatid exchange is unknown. This project will define this key missing structural and functional information in order to provide a mechanistic model for the function of SLF1-SLF2 complex.