Jackson Group

Research Summary

DNA is constantly damaged by environmental and internal processes within the body. Cell survival and genome integrity are promoted by DNA repair and associated processes, known as the DNA-damage response (DDR). Our research aims to characterise the cell biology and mechanisms of established and new DDR components and pathways, and to identify ways to translate this knowledge to better understand and treat human diseases.

Introduction

We have developed strong expertise in CRISPR-based gene-editing and screening technologies (top panel), which together with focused mechanistic studies, have allowed us to successfully interrogate and identify new players in DNA damage responses, including in clinically relevant settings.

For example, we have conducted genome-wide CRISPRi screens in the presence or absence of chemicals, such as formaldehyde, to identify factors involved in the repair of DNA-protein crosslinks (DPCs). Covalent DNA-protein cross-links (adducts) are toxic DNA lesions that block replication and transcription, and require repair by multiple pathways.

By comparing and contrasting hits arising from our genetic screens and using a novel method for the genome-wide mapping of DNA-protein adducts, we (in collaboration with Julian Stingele’s lab, Munich) discovered the first transcription-coupled DPC repair pathway (Carnie & Acampora et al, Nature Cell Biology, 2024). Defects in this pathway likely contribute to the severe neurological defects observed in Cockayne Syndrome patients.

Panel shows the recovery over time of RPE1 cells following formaldehyde treatment (induces DPCs), showing that in the absence of the Cockayne Syndrome gene CSB recovery of transcription is delayed, indicated by delayed appearance of EU staining (purple), a marker of RNA synthesis, and NPM1 staining (green), a marker of nucleolar ribonucleoprotein structures.

Prof Sir Steve Jackson PhD FRS FMedSci

Senior Group Leader,
Associate Director of Enterprise and Partnerships

Jackson Group external website

Biography

My academic research aims to better understand how cells detect and repair DNA damage and signal its presence to affect myriad aspects of cell biology. My laboratory has a strong track record of using a broad range of cell and molecular biological techniques and approaches, in both mammalian and yeast cells.

My discovery that DNA breaks trigger DNA-PK kinase activity established a paradigm for DNA damage detection and signalling, leading us to identify the first non-homologous end-joining (NHEJ) DNA-repair proteins. Subsequently, we identified and/or determined functions for these and other core NHEJ proteins, showing how they and additional DDR factors interact in regulated ways.

We have defined many aspects of the DDR, particularly those controlling and/or mediated by phosphorylation, ubiquitylation, sumoylation and/or chromatin modifications. In 1995, we found that DDR-enzyme-targeting compounds could selectively kill cancer cells, and that defects in some cause DNA-damage hypersensitivity in the absence of others.

Knowing that DDR defects occur in cancer, I founded KuDOS Pharmaceuticals: the world’s first DNA-repair company. KuDOS developed the innovative precision anti-cancer medicine olaparib/LynparzaTM that is enhancing and extending the lives of thousands of patients worldwide. My academic laboratory is currently further defining mechanisms of DNA repair and associated processes, with a view to delivering new biological insights and identifying new therapeutic opportunities for cancer and other diseases.

It is my belief that a deeper knowledge of DNA repair and DDR pathways will yield better understandings of diseases that arise when such pathways are impaired or deregulated.

Prof Sir Steve Jackson PhD FRS FMedSci

Senior Group Leader,
Associate Director of Enterprise and Partnerships

Visit the Jackson Group’s external site

Conflict of interest disclosure

Last revised: 19/07/2024

Company	Active	Research funding	Ownership	Royalty payments	Commitment to carry out work for a fee	Ad hoc reimbursed work	Travel	Gifts/other
AstraZeneca	Yes	Yes	No	No	No	Yes	No	No
GSK	Yes	Yes	No	No	No	Yes	No	No
Mission Therapeutics Ltd	Yes	Yes	Yes	No	Yes	No	No	No
Adrestia Therapeutics Ltd	Yes	Yes	Yes	No	Yes	No	No	No
Tailor Bio	Yes	No	Yes	No	No	Yes	No	No
Ahren Innovation Capital	Yes	No	Yes	No	No	Yes	No	No
Inflex	Yes	No	No	No	No	Yes	No	No