WIMM PI
Curriculum Vitae
Personal Data
Name:
Wojciech Niedzwiedz
Email:
wojciech.niedzwiedz@imm.ox.ac.uk
Current Position
2007-present Group Leader, Weatherall Institute of Molecular Medicine, Department of Molecular
Oncology, Oxford University.
Previous Positions
2002–2007 Postdoctoral fellow, Department of Medicine, Cambridge University/MRC-LMB,
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.
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 characterize 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 characterization 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
characterization 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 anticancer 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, neuro-degeneration 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
life-threatening 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 replicationmediated repair of stalled forks and in particular, how is the entire repair process executed and
what is the role of FA-associated 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
1. 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”). 10.2
2. 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
3. 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.
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. (article
featured in EMBO “news and views”). 9.2
5. Andrew N. Blackford, Rebekka A. Schwab, Wojciech Niedzwiedz. A novel ATRibute of
FANCM. 2010, Cell Cycle, Volume 9, Issue 8. 5.3
6. 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. 8.0
7. Oestergaard V, Langevin V, Kuiken J, Niedzwiedz W, Simpson L, Takata M, Sale J and
Patel KJ. Deubiquitination of FANCD2, but not of PCNA, is required for tolerance of DNA
damage. 2007, Molecular Cell. 28(5):798-809. 14.1
8. 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. 14.1
9. 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.
12.7
Ten 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. 14.1
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.
12.7
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. 8.0
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. 9.2
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. 7.6
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. 10.2
Markers of Esteem
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)
Fellow: Faculty of Genetics and Biotechnology, Warsaw University, Poland.
Current Grant Support
MRC Senior Research Fellowship