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

Publications

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
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 May 15 [Epub ahead of print]

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.

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Kate Dry
Chromatin determinants impart camptothecin sensitivity.

Puddu F, Salguero I, Herzog M, Geisler NJ, Costanzo V, Jackson SP.
EMBO Reports 2017 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.

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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.

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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.

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Kate Dry
Targeting DNA Repair in Cancer: Beyond PARP Inhibitors.

Brown JS, O'Carrigan B, Jackson SP, Yap TA. Cancer Discovery 7, 20-37

Germline aberrations in critical DNA-repair and DNA damage-response (DDR) genes cause cancer predisposition, whereas various tumors harbor somatic mutations causing defective DDR/DNA repair. The concept of synthetic lethality can be exploited in such malignancies, as exemplified by approval of poly(ADP-ribose) polymerase inhibitors for treating BRCA1/2-mutated ovarian cancers.

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Kate Dry
A novel somatic mutation achieves partial rescue in a child with Hutchinson-Gilford progeria syndrome.

Bar DZ, Arlt MF, Brazier JF, Norris WE, Campbell SE, Chines P, Larrieu D, Jackson SP, Collins FS, Glover TW, Gordon LB. Journal of Medical Genetics 54, 212-216

Hutchinson-Gilford progeria syndrome (HGPS) is a fatal sporadic autosomal dominant premature ageing disease caused by single base mutations that optimise a cryptic splice site within exon 11 of the LMNA gene. The resultant disease-causing protein, progerin, acts as a dominant negative. Disease severity relies partly on progerin levels.

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Kate Dry