The Steve Jackson Laboratory Website
Transformative discoveries in genome and cellular integrity

Publications

Validating the concept of mutational signatures with isogenic cell models

Zou X, Owusu M, Harris R, Jackson SP, Loizou JI, Nik-Zainal S. (2018)

Nature Communications 9(1):1744.
The diversity of somatic mutations in human cancers can be decomposed into individual mutational signatures, patterns of mutagenesis that arise because of DNA damage and DNA repair processes that have occurred in cells as they evolved towards malignancy. Correlations between mutational signatures and environmental exposures, enzymatic activities and genetic defects have been described, but human cancers are not ideal experimental systems—the exposures to different mutational processes in a patient’s lifetime are uncontrolled and any relationships observed can only be described as an association.

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Kate Dry
Targeting of NAT10 enhances healthspan in a mouse model of human accelerated aging syndrome

Balmus G, Larrieu D, Barros AC, Collins C, Abrudan M, Demir M, Geisler NJ, Lelliott CJ, White JK, Karp NA, Atkinson J, Kirton A, Jacobsen M, Clift D, Rodriguez R, Sanger Mouse Genetics Project, Adams DJ, Jackson SP.

Nature Communications (2018) 27 April [Epub ahead of print]
Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare, but devastating genetic disease characterized by segmental premature aging, with cardiovascular disease being the main cause of death. Cells from HGPS patients accumulate progerin, a permanently farnesylated, toxic form of Lamin A, disrupting the nuclear shape and chromatin organization, leading to DNA-damage accumulation and senescence.

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Kate Dry
Detection of functional protein domains by unbiased genome-wide forward genetic screening

Herzog M, Puddu F, Coates J, Geisler NJ, Forment JV, Jackson SP. (2018)
Scientific Reports [Epub ahead of print]
Genetic and chemo-genetic interactions have played key roles in elucidating the molecular mechanisms by which certain chemicals perturb cellular functions. Many studies have employed gene knockout collections or gene disruption/depletion strategies to identify routes for evolving resistance to chemical agents.

 

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Kate Dry
The non-homologous end joining protein PAXX acts to restrict HSV-1 infection

Trigg BJ, Lauer KB, Fernandes Dos Santos P, Coleman H, Balmus G, Mansur DS, Ferguson BJ. (2017)
Viruses 9, 342.

Herpes simplex virus 1 (HSV-1) has extensive interactions with the host DNA damage response (DDR) machinery that can be either detrimental or beneficial to the virus. Proteins in the homologous recombination pathway are known to be required for efficient replication of the viral genome, while different members of the classical non-homologous end-joining (c-NHEJ) pathway have opposing effects on HSV-1 infection. Here, we have investigated the role of the recently-discovered c-NHEJ component, PAXX (Paralogue of XRCC4 and XLF), which we found to be excluded from the nucleus during HSV-1 infection.

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Kate Dry
Parallel genome-wide screens identify synthetic viable interactions between the BLM helicase complex and Fanconi anemia.

Moder M, Velimezi G, Owusu M, Mazouzi A, Wiedner M, Ferreira da Silva J, Robinson-Garcia L, Schischlik F, Slavkovsky R, Kralovics R, Schuster M, Bock C, Ideker T, Jackson SP, Menche J, Loizou JI. (2017)
Nature Communications 8, 1238.

Maintenance of genome integrity via repair of DNA damage is a key biological process required to suppress diseases, including Fanconi anemia (FA). We generated loss-of-function human haploid cells for FA complementation group C (FANCC), a gene encoding a component of the FA core complex, and used genome-wide CRISPR libraries as well as insertional mutagenesis to identify synthetic viable (genetic suppressor) interactions for FA.

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Kate Dry
Deubiquitylating enzymes and drug discovery: emerging opportunities

Harrigan JH, Jacq X, Martin NM, and Jackson SP. (2018)
Nature Reviews Drug Discovery 17, 57-78

More than a decade after a Nobel Prize was awarded for the discovery of the ubiquitin–proteasome system and clinical approval of proteasome and ubiquitin E3 ligase inhibitors, first-generation deubiquitylating enzyme (DUB) inhibitors are now approaching clinical trials. However, although our knowledge of the physiological and pathophysiological roles of DUBs has evolved tremendously, the clinical development of selective DUB inhibitors has been challenging. In this Review, we discuss these issues and highlight recent advances in our understanding of DUB enzymology and biology as well as technological improvements that have contributed to the current interest in DUBs as therapeutic targets in diseases ranging from oncology to neurodegeneration.

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Kate Dry
Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer.

Asim M, Tarish F, Zecchini HI, Sanjiv K, Gelali E, Massie CE, Baridi A, Warren AY, Zhao W, Ogris C, McDuffus LA, Mascalchi P, Shaw G, Dev H, Wadhwa K, Wijnhoven P, Forment JV, Lyons SR, Lynch AG, O'Neill C, Zecchini VR, Rennie PS, Baniahmad A, Tavaré S, Mills IG, Galanty Y, Crosetto N, Schultz N, Neal D, Helleday T.
Nature Communications 8(1), 374

Emerging data demonstrate homologous recombination (HR) defects in castration-resistant prostate cancers, rendering these tumours sensitive to PARP inhibition. Here we demonstrate a direct requirement for the androgen receptor (AR) to maintain HR gene expression and HR activity in prostate cancer.

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Kate Dry
ATM, ATR, and DNA-PK: The trinity at the heart of the DNA damage response

Blackford AN, Jackson SP.
Molecular Cell, 66 (6), 801-817.

In vertebrate cells, the DNA damage response is controlled by three related kinases: ATM, ATR, and DNA-PK. It has been 20 years since the cloning of ATR, the last of the three to be identified. During this time, our understanding of how these kinases regulate DNA repair and associated events has grown profoundly, although major questions remain unanswered. Here, we provide a historical perspective of their discovery and discuss their established functions in sensing and responding to genotoxic stress.

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Kate Dry