1988-1991 University of Manchester Institute of Science and Technology, Bsc (Hons) Biochemistry

WIMM PI

CURRICULUM VITAE

Personal data

Name Peter McHugh

Education

1988-1991 University of Manchester Institute of Science and Technology, BSc (Hons) Biochemistry.

1992-1996 D.Phil Biochemistry (awarded May 1996), University of Oxford.

Research Career

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.

2010-present Deputy Director, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine.

2012-present Fellow, University College 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 UV-induced 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.

The future aims of our current studies

Our primary focus at the WIMM is a basic research programme that uses a combination of yeast genetics/molecular biology, mammalian cell biology and biochemistry to fully characterise DNA repair pathways acting on ICL-stalled replication forks. Here, we aim to gain an overview of mammalian replication-coupled ICL repair process and the contribution of several families of protein such as those that regulate homologous recombination and damage tolerance, including factors defective in Fanconi anemia (FA). Within this framework we aim for an extremely detailed characterisation of an exonuclease critical for replication-coupled ICL repair, SNM1A. This factor has the unusual property of digesting damaged DNA and it is likely that its key role in repairing damaged replication forks can be attributed to this. The N-terminus of SNM1A contains a number of highly conserved motifs that bind poly-ADP-ribose, ubiquitin and the replication sliding-clamp (PCNA complex), and we will elucidate how these domains cooperate to localise and regulate this important human DNA repair factor. We have also initiated studies on a little-studied helicase (HEL308) that is also required to repair damaged replication forks. Importantly, a number of genetic studies over the last few years have implicated HEL308 in cancer susceptibility, and mice lacking HEL308 have a Fanconi anemia-like phenotype suggesting that HEL308 might be an unassigned FA gene and important suppressor of haematological defects and cancer. We have strong collaborations with Opher Gileadi at the SGC in Oxford to solve the structures of the major repair proteins we study, and with Chris Schofield (Chemistry, Oxford) to identify small molecule inhibitors of these fork repair factors, which are be attractive candidates for tumour chemo-sensitisation.

How these aims contribute to the Understanding and/or Management of Human Disease

Loss of genomic stability directly contributes to the initiation and progression of malignancy. This is exemplified by cancer-prone disorders associated with defective replication-associated repair, for example Bloom’s Syndrome, Werner’s Syndrome and Fanconi anemia. Moreover, many cancer treatments rely on inflicting DNA damage, and the identification and characterisation of cellular factors that counteract this damage will reveal novel strategies for improving cancer treatment. We ultimately aim for a complete understanding of replication-coupled DNA repair pathways that act on interstand cross-links (ICLs), since this should have a significant impact on our understanding of the causes of cancer and reveal new strategies for treating the disease. Our strategy to achieve this and exploit our findings for the benefit of human health is three-fold. First, our basic research programme aims to identify the factors involved in replication-coupled ICL repair and to fully elucidate the molecular mechanism of the process. Second, we have initiated chemical-biology studies to identify inhibitors of key enzymes involved in replication-coupled repair, since interfering with these should sensitise/re-sensitise tumours to chemotherapeutics. Third we have strong links with the early-phase trials unit within Oxford. Here we have applied methods and approaches developed within our basic science programme to examine DNA repair and cell cycle control capacity in patient tumour samples in order to validate drug targets predictors of response. Ultimately we hope to marry all three areas, producing inhibitors to key factors that mediate chemo-resistance in cancer. Armed with the ability to take projects from target validation, though to identification of inhibitors in pre-clinical studies, we ultimately hope to bring new agents to early phase clinical trial where we will use our expertise to validate/elucidate drug mechanism in 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

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. 2014, 15;134(6):1495-503 (*co-corresponding authors).

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, 2013, 26;5(6):1714-24.

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-of-concept, 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.

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

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.

Sarkar S, Davies AA, Ulrich HD, McHugh PJ. DNA interstrand crosslink repair during G1 involves nucleotide excision repair and DNA polymerase z. 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 Boehringer Mannheim Prize (1991) for Clinical Biochemistry, UMIST.

1992-1996 Wellcome Trust Prize Studentship

2002 AACR Scholar-in-Training Award, Ortho Biotech, Inc.

2010 Deputy Director, Molecular Oncology, WIMM

Current Grant Support

MRC, 2014-2017, £886, 000.

ECMC Centre Grant (with several other Oncology/WIMM PIs) £3.5M