Professor Steve Smerdon

Supervisor Details

Contact Details

Institute of Cancer and Genomic Sciences, University of Birmingham

Scientific Background

Research Interests

For the last 20 years or so our primary interest has been in the significance of phosphorylation as a reversible molecular ‘switch’ for multi-protein complex assembly, with a major focus on signalling events that regulate the response to highly genotoxic double-stranded DNA breaks.

Our work has produced the first structures of 14-3-3 proteins (Cell 1997), FHA domains from Chk2 and its yeast orthologue Rad53 (Molecular Cell 2000 & 2002), the Polo-box domain from human Plk1 kinase (Cell 2003), Mob1-family proteins (Science 2013) and BRCT-repeat domains from human Brca1 and Mdc1 (NSMB 2004 & Cell 2005), all in complex with phosphorylated motifs from interacting partners. These structural firsts include a much anticipated study of the FHA-BRCT-repeat region of the Nbs1 signalling component of the DNA break repair ‘MRN’ complex (Cell 2009), More recently, we have used electron microscopy and ion-mobility mass spectrometry to describe the overall architecture of the core hetero-octameric Brca1-A histone deubiquitinase complex, providing some intriguing insights into substrate binding and mechanisms of phospho-dependent Brca1-mediated regulation (Cell Reports 2016).

Current projects build on and extend these previous studies and include:

Nbs1 structure-function relationships in interactions with Mdc1 and other factors.
Structure, assembly and regulation of Brca1 complexes.
Chk2 kinase activation and identification of novel substrates and effectors.
New chemical/synthetic biology and mass spectrometry approaches for identification of novel DNA damage-dependent interactions and functional DNA-damage phosphosite annotation.
Interplay between phosphorylation, ubiquitylation and sumoylation in cell proliferation and apoptosis.

Research Groups

Institute of Cancer and Genomic Sciences

Supervision Style

In three words or phrases: Relaxed, supportive, inclusive.

Provision of Training

Our research is multi-disciplinary in nature and so we draw from the experience of existing lab members and available expertise locally and in collaborating laboratories to provide the input and support necessary for development of a broadly based skill set relevant to modern structural molecular biology and biomedicine.

Progression Monitoring and Management

Whilst I take responsibility for overall management of the programme, I see research as a collective effort and expect all lab members to take a critical interest in all of our areas of interest.

Communication

Flexibility is key for good communication. I try to work around the students’ needs whilst ensuring that there are regular opportunities to provide guidance and, more importantly, to help the student develop their own ideas for progression of the project.

PhD Students can expect scheduled meetings with me:

In a group meeting

At least once per fortnight

In year 1 of PhD study

At least once per fortnight

In year 2 of PhD study

At least once per fortnight

In year 3 of PhD study

At least once per fortnight

The meetings will be face to face and I am usually contactable for an instant response 3 or 4 days per week.

Working Pattern

The timing of work in my lab is completely flexible, and (other than attending pre-arranged meetings), I expect students to manage their own time.

Notice Period for Feedback

I need at least 2 week’s notice to provide feedback on written work of up to 5000 words.

MIBTP Project Details

Current Projects (2025-26)

Primary supervisor for:

Reading, writing and molecular switching in the DNA-damage response

See the PhD Opportunities section to see if this project is currently open for applications via MIBTP.

Please Note: The main page lists projects via BBSRC Research Theme(s) quoted and then relevant Topic(s).

Reading, writing and molecular switching in the DNA-damage response

Secondary Supervisor(s): Professor Joanne Morris

University of Registration: University of Birmingham

BBSRC Research Themes: Understanding the Rules of Life (Structural Biology, Systems Biology)

Project Outline

How cells detect and respond to a bewildering variety of chemical, physical and environmental stimuli is a fundamental question in biology. Although much remains to be understood, it is clear that post-translational alteration of protein structure and behaviour through the timely addition of a variety of modifications such as phosphorylation, ubiquitylation, acetylation etc plays a central role. This is a simple but highly effective strategy since deposition - 'writing' - of the modification and its removal by a separate class of 'eraser' enzymes provides the desirable property of rapid reversibility. So, the modification itself acts as a molecular 'switch' that initiates or terminates downstream signalling events. How these modifications are generated and regulated, and how these switching mechanisms are manifested at the molecular level form our core interests and we investigate them using a highly multidisciplinary approach that enables us to relate structural and biochemical information to important physiological signalling mechanisms.

Our signalling network of choice is the DNA-damage response (DDR) for two main reasons. Firstly, disruption of the DDR is a characteristic of many human diseases including cancer, neurodegeneration, growth abnormalities and immunodeficiency and is the target of many therapeutic strategies. Secondly, its inherent complexity allows us to study how DNA-damage detection and repair are integrated with signalling to and from many other cellular processes such as metabolic state, cell-cycle, developmental stage, cell type-specific effects and the execution of transcriptional programmes.

Tens of thousands of sites of post-translational modifications (PTM) have been identified and mapped yet the functional significance of the vast majority remains unknown. PTMs can affect protein activity in many ways including promotion of conformational changes and triggering protein complex assembly through the activity of PTM-specific interaction modules or 'readers'. These effects are not mutually exclusive and our goal is to understand at the molecular level how multiple modifications can combine to generate the spectacular flexibility and precision in signal transduction that we observe in cells.

Projects in several relevant areas are available which will use a combination of emerging techniques in chemical/synthetic biology alongside classical structural biology methods and other biophysical, biochemical and cell-biological approaches to answer outstanding questions such as:

What is the molecular basis of cross-talk between signalling pathways that converge on specific post-translationally modified sequence motifs?
How are molecular barcodes generated from multiple and/or different types of modification interpreted to control cellular activities such as tethering and mobilisation of specific chromatin-associated signalling and repair complexes before, during and after DNA-damage.
How do post-translational modifications contribute to conformational rearrangements in macromolecular repair complexes and how are these effects influenced by interactions with 'reader' proteins?

Background references

Torres-Esteban et al (2024) ‘MDC1 mediates Pellino recruitment to sites of DNA double-strand breaks’ BioRxiv 2024.07.20.604390; doi: https://doi.org/10.1101/2024.07.20.604390.

Fournier, M. et al (2022) ‘KAT2-mediated acetylation switches the mode of PALB2 chromatin association to safeguard genome integrity’ Elife 11:e57736.

Kyrieleis, O.J.P. et al (2016) ‘Three-dimensional architecture of the human BRCA1-A histone deubiquitinase core complex’ Cell Reports, 17 3099-3106.

Lloyd, J. et al (2009) 'A supra-modular FHA/BRCT-repeat architecture mediates Nbs1 adaptor function in response to DNA-damage' Cell 139, 100-111.

Previous Projects (2024-25)

Co-supervisor on a project with Professor Andy Wilson.