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Molecular consequences of DNA damage and dysregulation

Dr. Sarah Aitken

 

Human cells endure a lifetime of exposure to endogenous and exogenous toxicants. For example, the gastrointestinal tract, including the liver, is exposed to a vast array of dietary metabolites, drugs, and other xenobiotics, as well as commensal and pathogenic organisms. These tissues are prone to accumulate damage due to their role in absorption and detoxification, which can cause mutations in both normal and diseased tissues (Brunner et al., Nature 2019; Ng et al., Nature 2021).

 

We recently discovered that some DNA lesions (damaged bases) segregate unrepaired into daughter cells for multiple generations, thereby generating combinatorial genetic diversity (Aitken et al., Nature 2020). Lesion segregation is a ubiquitous feature of DNA-damaging agents and has important implications for tumour evolution.

 

The overall aim of our interdisciplinary research group is to investigate mechanisms of cellular damage, and to understand their consequences for human health and disease. We use experimental and computational approaches to study genomic, cellular, and tissue-level responses to environmental and drug-induced insults. By exploiting genomics and pathomics techniques, we study normal and diseased cells and tissues to identify molecular mechanisms which are dysregulated in disease, including cancer.

 

Selected publications

 

  1. SWK Ng, FJ Rouhani, SF Brunner, N Brzozowska, SJ Aitken, M Yang, F Abascal, L Moore, E Nikitopoulou, L Chappell, D Leongamornlert, A Ivovic, P Robinson, T Butler, MA Sanders, N Williams, THH Coorens, J Teague, K Raine, AP Butler, Y Hooks, B Wilson, N Birtchnell, H Naylor, SE Davies, MR Stratton, I Martincorena, R Rahbari, C Frezza, M Hoare, PJ Campbell. Convergent somatic mutations in metabolism genes in chronic liver disease. Nature. 2021;598:473-478. https://www.nature.com/articles/s41586-021-03974-6

 

  1. SJ Aitken, CJ Anderson, F Connor, O Pich, V Sundaram, C Feig, TF Rayner, M Lukk, S Aitken, J Luft, E Kentepozidou, C Arnedo-Pac, SV Beentjes, SE Davies, RM Drews, A Ewing, VB Kaiser, A Khamseh, E López-Arribillaga, AM Redmond, J Santoyo-Lopez, I Sentís, L Talmane, AD Yates, Liver Cancer Evolution Consortium, CA Semple, N López-Bigas, P Flicek, DT Odom, MS Taylor. Pervasive lesion segregation shapes cancer genome evolution. Nature. 2020;583:265-270. https://www.nature.com/articles/s41586-020-2435-1

 

  1. E Kentepozidou, SJ Aitken, C Feig, K Stefflova, X Ibarra-Soria, DT Odom, M Roller, P Flicek. Clustered CTCF binding is an evolutionary mechanism to maintain topologically associating domains. Genome Biology. 2020;21:5. https://genomebiology.biomedcentral.com/articles/10.1186/s13059-019-1894-x

 

  1. SF Brunner, ND Roberts, LA Wylie, L Moore, SJ Aitken, SE Davies, M Sanders, P Ellis, C Alder, Y Hooks, F Abascal, MR Stratton, I Martincorena, M Hoare, PJ Campbell. Somatic mutations and clonal dynamics in healthy and cirrhotic human liver. Nature. 2019;574:538-542. https://www.nature.com/articles/s41586-019-1670-9

 

  1. F Connor, TF Rayner, SJ Aitken, C Feig, M Lukk, J Santoyo-Lopez, DT Odom. Mutational landscape of a chemically induced mouse model of liver cancer. Journal of Hepatology. 2018;69(4):840-850. https://www.journal-of-hepatology.eu/article/S0168-8278(18)32162-7/fulltext

 

  1. SJ Aitken*, X Ibarra-Sor­ia*, E Kentepozidou, P Flicek, C Feig, JC Marioni, DT Odom. CTCF maintains regulatory homeostasis of cancer pathways. Genome Biology. 2018;19:106. *SJA and XIS contributed equally. https://genomebiology.biomedcentral.com/articles/10.1186/s13059-018-1484-3