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Seminar Series

Date:
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Speaker:
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27 April 17
1-2pm
F2, Firth Court
Dr Marcus Wilson, Francis Crick Institute, London
The Structural Basis for chromatin recognition at DNA Double-Strand Breaks

Abstract: The molecular detail of how proteins recognize the histone code is poorly understood, especially within the context of an intact nucleosome core particle (NCP). DNA double-strand breaks (DSBs) elicit a histone modification cascade that controls DNA repair. This pathway culminates in the ubiquitylation of histone H2A on Lys-13 and Lys-15, an event that triggers the recruitment of DNA damage effector proteins such as 53BP1 and RNF169.

I will present our progress in understanding how 53BP1 and RNF169 proteins elegantly read the post-translational status of DNA damage adjacent chromatin. Using biochemical, biophysical and electron cryomicroscopy techniques we characterized how 53BP1 binds to a H4K20me2- and H2AK15ub-containing NCP. 53BP1 forms direct contacts with histone tail methylation and ubiquitylation modifications, as well as the nucleosome surface itself.  While methylation binding is limited to just the histone tail, A short peptidic UDR fragment of 53BP1 is highly ordered and mediates both ubiquitin site specificity and nucleosomal recognition. Furthermore, our currently unpublished results reveal that RNF169 also engages ubiquitylated nucleosomes, with a different but mutually exclusive binding mode compared to that of 53BP1. This structural and biochemical characterization reveals the basis of ubiquitin-dependent recruitment to DSB sites and illuminates how combinations of histone marks and nucleosomal elements cooperate to produce highly specific chromatin responses.

Bio: Marcus Wilson did his masters studies at the University of Oxford, UK before moving for his graduate studies with Dr. Jepser Svejstrup at the Cancer Research UK, Clare Hall laboratories in London, UK. During his PhD Marcus investigated the role of DNA-damage induced transcription blocking and subsequent RNAP ubiquitylation and degradation. Marcus then moved for a Postdoc in the lab of Prof. Daniel Durocher in the Lunenfeld-Tanenbaum research Institute in Toronto, Canada. There he started working on single particle cryo-electron microscopy; collaborating with Dr. John Rubinstein, at the SickKids research Institute In Toronto. The primary aim of his project has been to investigate the binding of DNA damage repair factors to chromatin. Since 2016 Marcus moved to the Crick Institute in London continuing to explore how chromatin proteins recognize the histone code and improving his cryo-EM skills in the lab of Dr. Alessandro Costa.

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