Title

Wojciech Niedzwiedz

DNA Repair and Replication Group

We are working towards elucidating how cells resolve replicative stress arising from endogenous and exogenous sources, and how failure to do so impacts on genome stability, cancer development and ageing.

Email: 
wojciech.niedzwiedz@oncology.ox.ac.uk
Telephone: 
+44 (0)1865 222671 / +44 (0)1865 222458 (PA)
PA: 
Penny Berry
Email PA: 
penny.berry@oncology.ox.ac.uk

Research Summary

Our research in genomic instability syndromes and development of cancer focuses on understanding the mechanisms disrupted in a childhood cancer predisposing syndrome named Fanconi Anaemia (FA). Children afflicted with FA show developmental defects, progressive bone marrow failure and have up to 1000 fold increased cancer risk. This underscores the essential role of this pathway in suppressing tumour formation.

The genes mutated in this syndrome encode a network of ‘caretaker’ proteins, which not only ensure that 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.

We are particularly interested in how the repair of damaged DNA is executed in the context of the replication fork, and how fork stability is achieved under stressful conditions..  To address these questions we are employing state-of-the art techniques that allows monitoring of DNA replication at the single molecule level in vivo (Figure 1). Using these approaches we aim to explain how the FA proteins function to promote DNA replication, and whether dysfunctional replication-mediated DNA repair is a common signal that drives FA disease progression to leukaemia.

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.

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

Biography

Wojciech Niedzwiedz is a Group Leader in the Department of Oncology, based at the Weatherall Institute of Molecular Medicine. He came to Oxford in 2007 after receiving a Senior International Research Fellowship from the Association for International Cancer Research to set up his own laboratory. In 2012 he was awarded a MRC Senior-Non Clinical Fellowship to continue his work on dissecting the FA tumour suppressor pathway.  He is a member of the Polish Radiation Research Society and the European Environmental Mutagen Society.

Publications

SELECTED PUBLICATIONS:

Broderick R, Nieminuszczy J, Baddock HT, RA Deshpande, Gileadi O, Paull TT, McHugh PJ, Niedzwiedz W. EXD2 promotes homologous recombination by facilitating DNA-end resection. Nat Cell Biol. 2016 Jan 25. doi: 10.1038/ncb3303.

Schwab RA, Nieminuszczy J, Shah F, Langton J, Lopez Martinez D, Liang C, Cohn MA, Gibbons RJ, Deans AJ, Niedzwiedz W. The Fanconi anaemia pathway maintains genome stability by coordinating replication and transcription. Mol Cell. 2015 60(3), pp. 351-361.

Higgs MR, Reynolds JJ, Winczura A, Blackford AN, Borel V, Miller ES, Zlatanou A, Nieminuszczy J, Ryan EL, Davies NJ, Stankovic T, Boulton SJ, Niedzwiedz W, Stewart GS. BOD1L is required to suppress deleterious resection of stressed replication forks. Mol Cell. 2015 Aug 6;59(3):462-77

Andrew N. Blackford, Jadwiga Nieminuszczy, Rebekka A. Schwab, Yaron Galanty, Stephen P. Jackson, Wojciech Niedzwiedz. TopBP1 interacts with BLM to maintain genome stability but is dispensable for preventing BLM degradation. 2015, Molecular Cell. S1097(15), doi;10:1016/j.molcel5351

Ronan Broderick, Jadwiga Nieminuszczy, Andrew N. Blackford, Alicja Winczura,  Wojciech Niedzwiedz. TOPBP1 recruits TOP2A to ultra-fine anaphase bridges to aid in their resolution. 2015, Nat. Communication. 6:6572 doi: 10.1038/ncomms7572.

Schwab RA, Nieminuszczy J, Shin-Ya K, Niedzwiedz W. FANCJ couples replication past natural fork barriers with maintenance of chromatin structure. J Cell Biol. 2013 Apr 1;201(1):33-48. (article featured in JCB and NCB “research highlights”).

Blackford AN, Schwab RA, Nieminuszczy J, Deans AJ, West SC, Niedzwiedz W. The DNA translocase activity of FANCM protects stalled replication forks. Hum Mol Genet. 2012 May 1;21(9):2005-16. 7.6

Schwab RA, Blackford AN, Niedzwiedz W. ATR activation and replication fork restart are defective in FANCM-deficient cells. 2010, The EMBO Journal 29(4): 806-18. (article featured in EMBO “news and views”).

Associated Researchers

Group Members

Jamie Langton, DPhil Student
Jadwiga Nieminuszczy, Postdoctoral Researcher
Elizabeth Smethurst, DPhil Student

About Us
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