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

Publications

Map of synthetic rescue interactions for the Fanconi anemia DNA repair pathway identifies USP48

Velimezi G, Robinson-Garcia L, Muñoz-Martínez F, Wiegant WW, Ferreira da Silva J, Owusu M, Moder M, Wiedner M, Rosenthal SB, Fisch KM, Moffat J, Menche J, Van Attikum H, Jackson SP and Loizou JI.

Nature Communications 11 June 2018 [Epub ahead of print]

Defects in DNA repair can cause various genetic diseases with severe pathological phenotypes. Fanconi anemia (FA) is a rare disease characterized by bone marrow failure, developmental abnormalities, and increased cancer risk that is caused by defective repair of DNA interstrand crosslinks (ICLs). Here, we identify the deubiquitylating enzyme USP48 as synthetic viable for FA-gene deficiencies by performing genome-wide loss-of-function screens across a panel of human haploid isogenic FA-defective cells (FANCA, FANCC, FANCG, FANCI, FANCD2).

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Kate Dry
ATM orchestrates the DNA-damage response to counter toxic non-homologous end-joining at broken replication forks

Balmus G, Pilger D, Coates J, Demir M, Sczaniecka-Clift M, Barros A, Woods M, Fu B,Yang F, Chen E, Ostermaier M, Stankovic T, Ponstingl H, Herzog M, Yusa K, Munoz-Martinez F, Durant ST, Galanty Y, Beli P, Adams DJ, Bradley A, Metzakopian E, Forment JV, Jackson SP. (2018).


BioRxiv
Mutations in the ATM tumor suppressor confer hypersensitivity to DNA-damaging agents. To explore genetic resistance mechanisms, we performed genome-wide CRISPR-Cas9 screens in cells treated with the DNA topoisomerase poison topotecan. Thus, we establish that loss of terminal components of the non-homologous end-joining (NHEJ) machinery or the BRCA1-A complex specifically confers topotecan resistance to ATM-deficient cells.

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Kate Dry
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