WIMM PI
CURRICULUM VITAE
Personal data
Name
Peter McHugh
Email
peter.mchugh@imm.ox.ac.uk
Current Postion
2010-present Deputy Director, Molecular Oncology Laboratories, Weatherall Institute of
Molecular Medicine.
2012-present Fellow, University College Oxford.
Previous Positions
1996-1997
Wellcome Trust Post Doctoral Research Associate, Department of Biochemistry,
University of Oxford.
1997-2001
Post-Doctoral Research Fellow, Cancer Research UK Drug-DNA Interactions
Research Group, Department of Oncology, University College London.
2001-2002
Royal Society University Research Fellow and Lecturer, Department of
Oncology, University College London.
2002-2008
Cancer Research UK Tenure-Track Scientist and Head, DNA Damage and
Repair Group, Molecular Oncology Laboratories, Weatherall Institute of
Molecular Medicine, University of Oxford.
2008-2010
Senior Group Leader (Tenured) and Head, DNA Damage and Repair Group,
Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine,
University of Oxford.
Research Achievements
There is strong motivation for studying DNA repair from a cancer prevention and treatment
standpoint. My doctoral work concerned the biochemical/chemical characterisation of UVinduced damage to DNA, which is important for understanding sunlight-induced carcinogenesis.
During my post-doctoral work I began to examine the cellular response to DNA interstrand
crosslinks (ICL), demonstrating that a critical repair-response to ICLs in yeast is triggered during
DNA replication, where forks encountering an ICL collapse. These findings were extended to
mammalian systems to demonstrate the evolutionary conservation of this core ICL response,
and I identified the mammalian XPF endonuclease as a key player in this pathway. This work
was recognised by the award of a Royal Society Research Fellowship within 4 years of the start
of my post-doctoral work. From 2003, my lab at the WIMM initially focused on further in-depth
investigations of ICL repair pathways in yeast, demonstrating how they elicit cell cycle
checkpoints and how the major repair pathways employed vary through the cell cycle in a series
of key publications. A major contribution here was the delineation of the first near-complete ICL
repair pathway that operates in G1 phase cells. More recently we have also investigated
mammalian models of ICL repair and recently demonstrated how an endonuclease complex
(XPF-ERCC1) cooperates with a specific exonuclease (SNM1A) to initiate ICL repair in human
cells. We have shown that the SNM1A protein is endowed with an unusual capacity to digest
heavily damaged DNA, perhaps explaining its critical role in ICL repair. Finally, in the last year
we have identified a pathway strongly reminiscent of the Fanconi anemia (FA) repair pathway in
budding yeast that we believe will accelerate research into the molecular basis of the repair
defect in FA patients.
Lay Summary of Research
Our genetic blueprint (genome) is contained within long, chromosomal molecules of DNA.
During our lifetime, the cells in many of our tissues are constantly dividing to replace old and
damaged cells. This is part of a natural renewal process. Before dividing, all cells must replicate
their DNA very accurately to prevent chromosomal changes that could lead to cancer and other
debilitating diseases, many associated with aging. Any abnormalities encountered in
chromosomal DNA during replication must be repaired to ensure that the genome is faithfully
duplicated. One of our main aims is to understand how the repair of damaged DNA is controlled
during the duplication of chromosomes, and to understand why potentially dangerous changes
in the behavior of cells and tissues occur when this process goes wrong. This has important
implications in our efforts to prevent cancer, and should also help to identify individuals who
might be at increased risk of developing cancer.
Another, related, aspect of our work focuses on improving cancer treatment. Many widely-used
cancer chemotherapy drugs, as well as the radiation employed in cancer treatment, kill tumour
cells by damaging their chromosomal DNA. For many patients treatment with drugs and
radiation produces a dramatic increase in survival, but unfortunately such treatment sometimes
fails. This might be due to the particular tumour not responding to therapy (being ‘resistant’), or
alternatively that following a good initial response further treatment fails, a process known as
‘acquired resistance’. In both cases, there is accumulating evidence that increased DNA repair
capacity is an important factor in the emergence of tumour resistance. With a deep
understanding of DNA repair processes we should be able to introduce new drugs that improve
the efficacy of these DNA damaging therapies and improve the prospects for many cancer
patients.
All Publications, last 5 years
Srivas R, Costelloe T, Sarkar S, Malta E, Sun S-M, Pool M, Licon C, van Welsem T, van
Leeuwen F, McHugh PJ, van Attikum H, Ideker T. A UV-Induced Genetic Network Links the
RSC Complex to Nucleotide Excision Repair and Shows Dose-Dependent Rewiring. Cell
Reports, in press
Hatch SB, Swift LP, Caporali S, Carter R, Hill EJ, Macgregor TP, D'Atri S, Middleton MR,
McHugh PJ*, Sharma RA*. XPF protein levels determine sensitivity of malignant melanoma
cells to oxaliplatin chemotherapy: Suitability as a biomarker for patient selection.Int J Cancer.
2013, in press (*co-corresponding authors).
Nguyen,G, Dexheimer TS, Rosenthal A, Chu W-K, Mosedale G, Bachrati C, Schultz L,
Sakurai M, Savitsky P, Abu M, McHugh PJ, Bohr V, Harris CC, Jadhav A, Gileadi O,
Maloney DJ, Simeonov A, Hickson ID. A small molecule inhibitor of the BLM helicase
modulates chromosome stability in human cells. Chemistry and Biology, 2013, 20(1):55-62.
McHugh PJ, Ward TA, Chovanec M. A prototypical Fanconi anemia pathway in lower
eukaryotes? Cell Cycle, 2012, 11: 3739-44
Ward TA, Dudášová Z, Sarkar S, Bhide MR, Vlasáková D, Chovanec M, McHugh PJ.
Components of a fanconi-like pathway control pso2-independent DNA interstrand crosslink
repair in yeast. PLoS Genet. 2012;8: e1002884
Sengerová B, Allerston CK, Abu M, Lee SY, Hartley J, Kiakos K, Schofield CJ, Hartley JA,
Gileadi O, McHugh PJ. Characterization of the human SNM1A and SNM1B/Apollo DNA
repair exonucleases. J Biol Chem. 2012 ;287:26254-67
Olsen AL, Davies JM, Medley L, Breen D, Talbot DC, McHugh PJ. Quantitative analysis of
survivin protein expression and its therapeutic depletion by an antisense oligonucleotide in
human lung tumors. Mol Therapy 2012; 1, e30.
Orchestrating the nucleases involved in DNA interstrand cross-link (ICL) repair. Sengerová B,
Wang AT, McHugh PJ. Cell Cycle. 2011; 10(23):3999-4008.
Wang AT, Sengerová B, Cattell E, Inagawa T, Hartley JM, Kiakos K, Burgess-Brown N, Enzlin
JH, Schofield CJ, Gileadi O, Hartley JA, McHugh PJ. Human SNM1A and XPF-ERCC1
collaborate to initiate DNA interstrand cross-link repair. Genes and Development 2011; 25
(17):1859-70.
Tafel AA, Wu L, McHugh PJ. Human HEL308 localizes to damaged replication forks and
unwinds lagging-strand structures. J Biol Chem. 2011; May 6;286(18):15832-40
Ashton TM, Mankouri HW, Heidenblut A, McHugh PJ, Hickson ID. Pathways for Holliday
Junction Processing during Homologous Recombination in Saccharomyces cerevisiae. Mol
Cell Biol. 2011; 31 (9):1921-33.
Sarkar S, Kiely R, McHugh PJ. The Ino80 chromatin-remodeling complex restores chromatin
structure during UV DNA damage repair. J. Cell Biol. 2010; 13;191(6):1061-8.
The SNM1/Pso2 family of ICL repair nucleases: From yeast to man. Cattell E, Sengerová B,
McHugh PJ. Environ Mol Mutagen. 2010; 51(6): 635-45.
Tumor survivin is downregulated by the antisense oligonucleotide LY2181308: a proof-ofconcept, first-in-human dose study. Talbot DC, Ranson M, Davies J, Lahn M, Callies S,
André V, Kadam S, Burgess M, Slapak C, Olsen AL, McHugh PJ, de Bono JS, Matthews J,
Saleem A, Price P. Clin Cancer Res. 2010; 16 (24): 6150-8.
Bhagwat N, Olsen AL, Wang AT, Hanada K, Stuckert P, Kanaar R, D’Andrea AD, Niedernhofer
LJ, McHugh, PJ. XPF-ERCC1 participates in the Fanconi anemia pathway of crosslink
repair. Mol. Cell. Biol. 2009; 29 (24); 6427-37.
Wang AT, McHugh, PJ. Apollo: a healer of the genome? Cell Cycle. 2009 8:1980-1
Hazrati A, Ramis-Castelltort M, Sarkar S, Barber LJ, Schofield CJ, Hartley JA, McHugh PJ.
Human SNM1A suppresses the DNA repair defects of yeast pso2 mutants. DNA Repair
(Amst). 2008; 7:230-8.
Lehoczký P, McHugh PJ, Chovanec M. DNA interstrand cross-link repair in Saccharomyces
cerevisiae. FEMS Microbiol Rev. 2007 31:109-33.
Kiakos K, Sato A, Asao T, McHugh PJ, Lee M, Hartley JA. DNA sequence selective adenine
alkylation, mechanism of adduct repair, and in vivo antitumor activity of the novel achiral
seco-amino-cyclopropylbenz[e]indolone analogue of duocarmycin AS-I-145. Mol Cancer
Ther. 2007; 6:2708-18.
Ten Key Publications Throughout Career
Ward TA, Dudášová Z, Sarkar S, Bhide MR, Vlasáková D, Chovanec M, McHugh PJ.
Components of a fanconi-like pathway control Pso2-independent DNA interstrand crosslink
repair in yeast. PLoS Genet. 2012;8: e1002884
Wang AT, Sengerová B, Cattell E, Inagawa T, Hartley JM, Kiakos K, Burgess-Brown N, Enzlin
JH, Schofield CJ, Gileadi O, Hartley JA, McHugh PJ. Human SNM1A and XPF-ERCC1
collaborate to initiate DNA interstrand cross-link repair. Genes and Development 2011; 25
(17):1859-70.
Tafel AA, Wu L, McHugh PJ. Human HEL308 localizes to damaged replication forks and
unwinds lagging-strand structures. J Biol Chem. 2011; May 6;286(18):15832-40.
Sarkar S, Kiely R, McHugh PJ. The Ino80 chromatin-remodeling complex restores chromatin
structure during UV DNA damage repair. J. Cell Biol. 2010; 13;191(6):1061-8.
Bhagwat N, Olsen AL, Wang AT, Hanada K, Stuckert P, Kanaar R, D’Andrea AD, Niedernhofer
LJ, McHugh, PJ. XPF-ERCC1 participates in the Fanconi anemia pathway of crosslink
repair. Mol. Cell. Biol. 2009; 29 (24); 6427-37.
Sarkar S, Davies AA, Ulrich HD, McHugh PJ. DNA interstrand crosslink repair during G1
involves nucleotide excision repair and DNA polymerase . EMBO J. 2006; 25(6):1285-94.
Hartley JA, Spanswick VJ, Brooks N, Clingen PH, McHugh PJ, Hochhauser D, Pedley RB,
Kelland LR, Alley MC, Schultz R, Hollingshead MG, Schweikart KM, Tomaszewski JE,
Sausville EA, Gregson SJ, Howard PW, Thurston DE. SJG-136 (NSC 694501), a novel
rationally designed DNA minor groove interstrand cross-linking agent with potent and broad
spectrum antitumor activity: part 1: cellular pharmacology, in vitro and initial in vivo antitumor
activity. Cancer Res. 2004; 64(18): 6693-9.
De Silva IU, McHugh PJ, Clingen PH, Hartley JA. Defining the roles of nucleotide excision
repair and recombination in the repair of DNA interstrand cross-links in mammalian cells. Mol
Cell Biol. 2000; 20(21): 7980-90.
McHugh PJ, Sones WR, Hartley JA. Repair of intermediate structures produced at DNA
interstrand cross-links in Saccharomyces cerevisiae. Mol Cell Biol. 2000; 20(10):3425-33.
McHugh PJ, Gill RD, Waters R, Hartley JA. Excision repair of nitrogen mustard-DNA adducts in
Saccharomyces cerevisiae. Nucleic Acids Res. 1999; 27: 3259-66.
Honours and Awards
1991
1992-1996
2002
2010
Boehringer Mannheim Prize (1991) for Clinical Biochemistry, UMIST.
Wellcome Trust Prize Studentship
AACR Scholar-in-Training Award, Ortho Biotech, Inc.
Deputy Director, Molecular Oncology, WIMM
Current Grant Support
MRC, 2014-2017, £886, 000.
ECMC Centre Grant (with several other Oncology/WIMM PIs) £3.5M