Curriculum Vitae
Name:
Wojciech Niedzwiedz
Address:
WIMM, Medical Oncology Department
Oxford University, Oxford, OX3 9DS
Email:
Tel/Fax:
wojciech.niedzwiedz@imm.ox.ac.uk
+44 1865 222 671
Education:
Ph.D. Silesian University/Institute of Nuclear Physics. Thesis title: Characterisation of
DNA damage induced by various LET radiation.
M.Sc. Jagiellonian University, Faculty of Molecular Biology, Department of Biochemistry
and Biophysics, 1994. Thesis title: Measurement of oxygen diffusion and free radicals
production in liquids with the application of ESR technique.
Awards:
2011 WIMM MRC Senior Research Fellowship
2007 Association for International Cancer Research – Senior International
Cancer Research Fellowship (only one awarded a year)
2007 - Winner of the international competition for a Group Leader position
at the International Institute for Molecular and Cell Biology, Warsaw,
Poland.
2001 Silesian University Research Board Award /for the most worthy PhD
work/
1997 Award of the Batory Foundation
1990 -1994 Jagiellonian University, scientific scholarship (top 5% students)
Honours:
Fellow: Faculty of Genetics and Biotechnology, Warsaw University, Poland.
Professional work experience:
Positions
2007-present Group Leader, Weatherall Institute of Molecular Medicine, Department of
Molecular Oncology, Oxford University.
2002–2007
Postdoctoral fellow, Department of Medicine, Cambridge University/MRCLMB, Cambridge, UK. Project: Dissecting the Fanconi anaemia tumour suppressor
pathway.
2000 - 2001 Deputy Director Department of Radiation and Environmental Biology,
Institute of Nuclear Physics, Krakow, Poland.
Group Leader Pre-clinical Research and Neutron Therapy Group. Department of
Radiation and Environmental Biology, Institute of Nuclear Physics, Krakow, Poland.
1996-2000
PhD student Department of Radiation and Environmental Biology, Institute
of Nuclear Physics, Krakow, Poland.
Grants:
AICR International Cancer Research Fellowship (£900K/2007-2012)
Polish State Committee for Scientific Research Grant GR 2784 (£150K/2009-2012)
Union for International Cancer Control (50 000 USD/2011-20112)
MRC (£600K 2012-2017)
Research Achievements
Much of my scientific activity could be viewed as being of basic science and discovery. I
have always maintained an interest in understanding the molecular mechanisms of
genomic instability and DNA damage repair. As a postdoctoral fellow I have shown that a
close interplay of the FA proteins with homologous recombination and translesion DNA
synthesis is required for efficient crosslink repair. This important discovery brought about a
paradigm shift in the FA field by firmly establishing that the FA pathway links in with and
coordinates the key replication repair processes in a combined process to maintain
genome stability. I also showed, for the first time, that the FA pathway is important for the
mutational repair of endogenously generated abasic sites, implying a general role for the
FA proteins in dealing with lesions capable of impeding replication forks. Following this
lead I focused on how the FA nuclear complex could recognise stalled replication forks
and this work allowed me to identify a new FA protein, now known as FANCM. Next I have
delineated the molecular mechanism by which FANCM promotes maintenance of stalled
replisomes. Recently, I have also characterised the molecular mechanism by which
another FA associated helicase – FANCJ promotes genome stability. This is through
counteracting fork stalling in the presence of replication barriers and preventing chromatin
compaction associated with perturbed replication.
Interfering with the process of DNA replication is at the heart of a large class of anticancer
agents, it is conceivable therefore, that better insight in to the mechanisms that act to
replicate damaged DNA will help to improve our understanding of clinical effectiveness
and side effects of these agents and as such improve cancer chemotherapy.
What are the Future Aims of Your Current Group
The future of my group is to continue studying the overall function of the FA proteins, and
in particular the two FA–associated helicases FANCM and FANCJ. To this end, I am
planning to simultaneously adopted a three-pronged approach that involves:
a) The use of highly innovative genetic-proteomic based approaches to identify novel
components of the FA pathway and characterise their role in normal development and
DNA damage response. To this end, we have recently developed a versatile eTAP
system (Endogenous Tagging for Tandem Affinity purification with Strep II-Flag tag).
b) Comprehensive identification and characterisation of chromosomal landscape
recognized by the FA proteins and/or modified in their absence (in particular FANCM
and FANCJ). (i.e. origins of replication, telomeres, recombination hot-spots, structured
DNA, etc). This should shed light on the role of the FA pathway in genome
maintenance by facilitate the characterisation of the FA-epigenome interaction.
c) Analysis of the anatomy of a stalled replication fork in order to delineate the role of
FANCM and FANCJ in promoting fork maintenance and its clinical consequences;
How do These Aims Contribute to the Understanding and/or Management of Human
Disease
A longer-term goal of my research is to translate laboratory findings into the development
of novel therapies for individuals with FA and related conditions, and also to make
significant contributions to our understanding of the critical role of genomic stability
pathways in normal human development and tumourgenesis.
The observation of mutation in BRCA2, ATM and FANCM in both genetic and sporadic
cancers, combined with discovery of hypersensitivity to PARP inhibitors in BRCA mutant
cell lines, has opened up the concept of ‘synthetic lethality’ with some striking clinical
success in ovarian and breast cancer. It is therefore of great importance from a
therapeutic point of view to understand the mechanisms employed by normal and tumour
cells during proliferation to counter the adverse effect of DNA damaging agents. Such
knowledge may lead to the development of novel anti-cancer therapeutic approaches. In
line with this, our recent discovery that FANCM-deficient cells are sensitive to clinically
tested inhibitors to ATM and PARP could substantially expand this approach. It offers the
possibility of tumour specific therapies with low systemic toxicity. It may also provide the
rational basis for developing new drugs targeting FANCM.
Moreover, our data suggest that FANCM promotes chromosomal stability also by
mechanisms that are outside its role within the FA pathway. In line with this, FANCM
display a broader sensitivity pattern to DNA damaging agents than any of the other FA
mutants. This includes widely used drugs such as Hydroxyurea and Camptothecin.
Although, non-selective FA inhibitors are already available, their mode of action has not
been fully determined. Rationally designed FANCM inhibitors are therefore more likely to
be more specific/potent and applicable to clinical assessment. Given the above, in the
future we aim to develop novel FANCM inhibitors for potential use in anti-cancer therapy.
Lay Summary of Research
DNA is the store of genetic information in all living things. For an organism to develop,
stay healthy and reproduce itself, its DNA needs to be copied exactly, without any
mistakes. Damaged DNA must also be properly repaired for cells to survive. Since DNA
molecules are very large and complex, this is a challenging task that requires many
different proteins. Some people are born with inherited defects in the ability of their cells to
make proteins required for DNA replication or repair. Consequently, these individuals are
prone to a number of very serious conditions including blood disorders, neurodegeneration and cancer. For example, people whose cells contain two mutated copies of
FA genes (one inherited from their mother and one from their father) develop a lifethreatening disease called Fanconi Anaemia. Homozygous mutations in some FA gens
have been found in breast cancer and as a polymorphic risk factor in osteosarcoma. This
tells us that FA pathway must act somehow to suppress tumour development. Recently
we have identified a novel function for FA proteins in response to replicative stress
whereby they orchestrates the temporal and spatial repair of stalled forks. At this stage
however, we don’t fully understand how FA proteins do this job, or even what sort of DNA
damage they recognize. Consequently, one of the outstanding questions in the field is to
determine how the FA pathway promotes replication-mediated repair of stalled forks and
in particular, how is the entire repair process executed and what is the role of FAassociated helicases in this regard? It is conceivable that better insight into the role of the
FA proteins in genome stability maintenance will shed light on how DNA repair acts to
facilitate normal development, and suppress devastating haematological and malignant
conditions.
List of Publications over the last 5 years
1.
Keiko Yata, Jean-Yves Bleuyard, Ryuichiro Nakato, Christine Ralf, Yuki Katou,
Rebekka A Schwab, Wojciech Niedzwiedz, Katsuhiko Shirahige and Fumiko Esashi.
BRCA2 coordinates the activities of cell cycle kinases to promote genome stability. Cell
Rep. 2014 Jun 12;7(5):1547-59. (7.2)
2. 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”). (9.7)
3.
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. (6.7)
4.
Schwab RA, Niedzwiedz W. Visualization of DNA replication in the vertebrate
model system DT40 using the DNA fiber technique. 2011, J Vis Exp. (56):e3255.
5.
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”). (10.7)
6.
Andrew N. Blackford, Rebekka A. Schwab, Wojciech Niedzwiedz. A novel
ATRibute of FANCM. 2010, Cell Cycle, Volume 9, Issue 8. (5)
7.
Niedzwiedz W, Rosado IV, Alpi AF, Patel KJ. The Walker B motif in avian FANCM
is required to limit sister chromatid exchanges but is dispensable for DNA crosslink repair.
2009, Nucleic Acids Res, 37(13):4360-70. (8.8)
Key Publications Throughout your Career
1.
Niedzwiedz W, Mosedale G, Johnson M, Ong CY, Pace P, Patel KJ. Fanconi
anaemia gene FANCC promotes homologous recombination and error-prone DNA repair.
2004 Molecular Cell. 27;15(4):607-20. (14.5)
2.
Niedzwiedz W, Mosedale G, Alpi A, Perrina F, Pereira-Leal JB, Johnson M,
Langevin F, Pace P, Patel KJ. The vertebrate Hef ortholog is a component of the Fanconi
anemia tumor-suppressor pathway. 2005, Nature Structural and Molecular Biology,
12(9):763-71. (11.7)
3.
Niedzwiedz W, Rosado IV, Alpi AF, Patel KJ. The Walker B motif in avian FANCM
is required to limit sister chromatid exchanges but is dispensable for DNA crosslink repair.
2009, Nucleic Acids Res, 37(13):4360-70. (8.8)
4.
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.
(10.7)
5.
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. (6.7)
6.
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. (9.7)
Peer review:
Journals: PLoS Genetics, Plos One, Molecular and Cellular Biology, Oncogene, Cell
Reports, Cell Death and Differentiation, Scientific Reports, Biochemical Journal,
BioTechniques.
Funding agencies: BBSRC, Yorkshire Cancer Research