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

Publications

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.

Read More
Kate Dry
Deubiquitylating enzymes and drug discovery: emerging opportunities

Harrigan JH, Jacq X, Martin NM, and Jackson SP. (2017)
Nature Reviews Drug Discovery [Epub ahead of print]

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.

Read More
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.

Read More
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.

Read More
Kate Dry
PGBD5 promotes site-specific oncogenic mutations in human tumors.

Henssen AG, Koche R, Zhuang J, Jiang E, Reed C, Eisenberg A, Still E, MacArthur IC, Rodríguez-Fos E, Gonzalez S, Puiggròs M, Blackford AN, Mason CE, de Stanchina E, Gönen M, Emde AK, Shah M, Arora K, Reeves C, Socci ND, Perlman E, Antonescu CR, Roberts CWM, Steen H, Mullen E, Jackson SP, Torrents D, Weng Z, Armstrong SA, Kentsis A.
Nature Genetics 2017, 49, 1005-1014

Genomic rearrangements are a hallmark of human cancers. Here, we identify the piggyBac transposable element derived 5 (PGBD5) gene as encoding an active DNA transposase expressed in the majority of childhood solid tumors, including lethal rhabdoid tumors. Using assembly-based whole-genome DNA sequencing, we found previously undefined genomic rearrangements in human rhabdoid tumors.

Read More
Kate Dry
Chromatin determinants impart camptothecin sensitivity

Puddu F, Salguero I, Herzog M, Geisler NJ, Costanzo V, Jackson SP. (2017)
EMBO Reports 18, 1000-1012.

Camptothecin-induced locking of topoisomerase 1 on DNA generates a physical barrier to replication fork progression and creates topological stress. By allowing replisome rotation, absence of the Tof1/Csm3 complex promotes the conversion of impending topological stress to DNA catenation and causes camptothecin hypersensitivity. Through synthetic viability screening, we discovered that histone H4 K16 deacetylation drives the sensitivity of yeast cells to camptothecin and that inactivation of this pathway by mutating H4 K16 or the genes SIR1-4 suppresses much of the hypersensitivity of tof1∆ strains towards this agent.

Read More
Kate Dry
Genetic variants associated with mosaic Y chromosome loss highlight cell cycle genes and overlap with cancer susceptibility

Wright DJ, Day FR, Kerrison ND, Zink F, Cardona A, Sulem P, Thompson DJ, Sigurjonsdottir S, Gudbjartsson DF, Helgason A, Chapman JR, Jackson SP, Langenberg C, Wareham NJ, Scott RA, Thorsteindottir U, Ong KK, Stefansson K, Perry JR.
Nature Genetics 2017 49(5):674-679

The Y chromosome is frequently lost in hematopoietic cells, which represents the most common somatic alteration in men. However, the mechanisms that regulate mosaic loss of chromosome Y (mLOY), and its clinical relevance, are unknown. We used genotype-array-intensity data and sequence reads from 85,542 men to identify 19 genomic regions (P < 5 × 10-8) that are associated with mLOY.

Read More
Kate Dry
Genome-wide genetic screening with chemically mutagenized haploid embryonic stem cells.

Forment JV, Herzog M, Coates J, Konopka T, Gapp BV, Nijman SM, Adams DJ, Keane TM, Jackson SP. Nature Chemical Biology 13, 12-14.

In model organisms, classical genetic screening via random mutagenesis provides key insights into the molecular bases of genetic interactions, helping to define synthetic lethality, synthetic viability and drug-resistance mechanisms. The limited genetic tractability of diploid mammalian cells, however, precludes this approach.

Read More
Kate Dry