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

Publications

Shieldin complex promotes DNA end-joining and counters homologous recombination in BRCA1-null cells

Dev H, Chiang TW, Lescale C, de Krijger I, Martin AG, Pilger D, Coates J, Sczaniecka-Clift M, Wei W, Ostermaier M, Herzog M, Lam J, Shea A, Demir M, Qian Wu Q, Yang F, Fu B, Lai Z, Balmus G, Belotserkovskaya R, Serra V, O’Connor MJ, runa A, Beli P, Pellegrini L, Caldas C, Deriano L, Jacobs JJL, Galanty Y and Jackson SP.

Nature Cell Biology 18 July 2018 [EPub ahead of print]

BRCA1 deficiencies cause breast, ovarian, prostate and other cancers, and render tumours hypersensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. To understand the resistance mechanisms, we conducted whole-genome CRISPR–Cas9 synthetic-viability/resistance screens in BRCA1-deficient breast cancer cells treated with PARP inhibitors. We identified two previously uncharacterized proteins, C20orf196 and FAM35A, whose inactivation confers strong PARP-inhibitor resistance.

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Kate Dry
Inhibition of the acetyltransferase NAT10 normalizes progeric and aging cells by rebalancing the Transportin-1 nuclear import pathway

Larrieu D, Viré E, Robson S, Breusegem SY, Kouzarides T, Jackson SP.

Science Signaling 11, eaar5401

Cells from patients with Hutchinson-Gilford progeria syndrome (HGPS) have defects in nuclear architecture and function that lead to premature cellular senescence, aging, and early death. Larrieu et al. (see the Focus by Wilson) found that inhibition or depletion of the acetyltransferase NAT10 rescued many of the phenotypes of HGPS patient cells by destabilizing microtubules, which reversed the abnormal cytoplasmic accumulation of the nuclear importer Transportin-1 (TNPO1). This restored proper assembly of the nuclear pore complex, import of nuclear proteins, chromatin organization, and gene expression patterns.

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Kate Dry
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