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Wojciech Niedzwiedz

DNA Replication and Repair

Laboratory Members

  • Andrew Blackford
  • Kowcee Jalal
  • Jadwiga Nieminuszczy
  • Rebekka Schwab

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Department Weatherall Institute of Molecular Medicine
Wojciech Niedzwiedz

Wojciech Niedzwiedz

DNA is continuously exposed to endogenous and exogenous agents that can create lesions disrupting duplication of the genome. Mounting evidence suggests that defects in DNA replication are the major source of spontaneous chromosome instability, a recognised causative factor in cancer. This is underscored by several genome instability and cancer predisposing human diseases, one of them being Fanconi Anaemia (FA).

FA is a rare childhood cancer predisposing syndrome, characterised by developmental defects and progressive bone marrow failure. As a consequence, children with FA often develop pancytopenia, and ultimately most FA patients die at a young age of haematological diseases.

The genes mutated in this syndrome encode a network of ‘caretaker’ proteins, which not only ensure that our DNA is accurately copied but also prevent replication failure and associated genomic instability. Consequently, a properly functioning FA pathway is important for normal development, haematopoiesis and suppression of solid tumours in everyone, and as such underscores the importance of research in this area. 

Interestingly, cells from FA patients are also hypersensitive to DNA damaging agents that link two strands of DNA together, forming interstrand crosslinks (ICLs) and blocking DNA replication. This implies that the FA pathway is critical for removal of such lesions. This is important, as ICL inducing agents are the most widely used drugs in cancer therapy. 

Despite the critical role of ICLs in anti-cancer therapy the mechanisms by which higher vertebrate cells overcome ICL-induced replication blocks remains to be fully understood.
 The research interest of my group focuses on elucidating how the repair of damaged DNA is executed in the context of the replication fork, and how fork stability is achieved under stressful conditions. We are particularly interested in the molecular function of the FA proteins in these processes. 
To address these questions we are employing different techniques to monitor aspects of DNA replication. Among these techniques, DNA fiber analysis allows the monitoring of DNA replication at the single molecule level (Figure 1). Using these approaches we aim to explain how the FA proteins promote DNA replication under stressful conditions, and whether dysfunctional replication-mediated DNA repair is a common signal that drives FA disease progression to leukemia.
 
A long-term goal of our research is to elucidate the FA-dependent mechanism required to suppress devastating haematological and malignant conditions and translate our basic laboratory findings into the development of novel therapies for cancer.
 
Figure1.png

Figure 1. (A) Cartoon depicts the DNA fiber labelling procedure. (B) Examples of various replication structures that can be visualised with this technique. (C) Representative images showing colocalisation of γH2AX (red) and CldU (green) foci in WT DT40 and ΔFANCM cells treated with CPT. (D) Representative images showing increased Rad51 foci formation in FANCM-depleted cells treated with HU.