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MRC Toxicology Unit

 

Unit Programme: Chromatin control of environmental stress response

Programme Leader Track: Dr Ritwick Sawarkar

Cells respond to environmental stress and toxins by mounting an adaptive stress response in order to survive stressful conditions. Transcriptional control is a major regulatory layer that determines the strength, the duration and persistence of cellular stress response. Transcription factors, chromatin modifications and non-coding RNA influence the transcriptional response to environmental stress. The molecular mechanisms by which chromatin exerts control over stress response is the main focus of the Unit programme. We aim to address the following questions:

(i) Which cellular pathways sense environmental stress/ toxins and signal to the genome?

(ii) How does chromatin interpret the information about cellular health and toxic exposure determining the transcriptional response to stress?

(iii) How does the transcriptional response adapt cellular phenotypes to survive the stress?

We study these three questions in the context of cellular exposure to environmental stress as well as small-molecule therapeutics in collaboration with pharmaceutical companies.  Our approaches include genomics, single-cell transcriptomics, proteomics, chromatin biochemistry as well as genome-wide screening to identify novel components of stress-response pathways. Discovery-driven global approaches in mammalian cells are further validated by in vitro reconstitution experiments and mouse genetic models. We aim to gain novel insights and mechanistic understanding of transcriptional response to stress and toxins.

Key Publications:

Antonova A, Hummel B, Khavaran A, Redhaber DM, Aprile-Garcia F, Rawat P, Gundel K, Schneck M, Hansen EC, Mitschke J, Mittler G, Miething C, Sawarkar R. ‘Heat-Shock Protein 90 Controls the Expression of Cell-Cycle Genes by Stabilizing Metazoan-Specific Host-Cell Factor HCFC1.’ Cell Rep. 2019 Nov 5;29(6):1645-1659.e9. doi: 10.1016/j.celrep.2019.09.084.PMID:31693902

Aprile-Garcia F, Tomar P, Hummel B, Khavaran A, Sawarkar R. ‘Nascent-protein ubiquitination is required for heat shock-induced gene downregulation in human cells.’ Nat Struct Mol Biol. 2019 Feb;26(2):137-146. doi: 10.1038/s41594-018-0182-x. Epub 2019 Feb 4. PMID: 30723328

Irmak D, Fatima A, Gutiérrez-Garcia R, Rinschen MM, Wagle P, Altmüller J, Arrigoni L, Hummel B, Klein C, Frese CK, Sawarkar R, Rada-Iglesias A, Vilchez D. ‘Mechanism suppressing H3K9 trimethylation in pluripotent stem cells and its demise by polyQ-expanded huntingtin mutations.’ Hum Mol Genet. 2018 Dec 1;27(23):4117-4134. doi: 10.1093/hmg/ddy304. PMID:30452683

Vincenz-Donnelly L, Holthusen H, Körner R, Hansen EC, Presto J, Johansson J, Sawarkar R, Hartl FU, Hipp MS. ‘High capacity of the endoplasmic reticulum to prevent secretion and aggregation of amyloidogenic proteins.’ EMBO J. 2018 Feb 1;37(3):337-350. doi: 10.15252/embj.201695841. Epub 2017 Dec 15. PMID:29247078

Hummel, B., Hansen, E.C., Yoveva, A., Aprile-Garcia, F., Hussong, R., and Sawarkar, R. (2017). The evolutionary capacitor HSP90 buffers the regulatory effects of mammalian endogenous retroviruses. Nature structural & molecular biology 24, 234-242.

Sawarkar R, Sievers C and Paro R (2012) Hsp90 globally targets paused RNA polymerase to regulate gene expression in response to stimuli. Cell. 149(4):807-18.