Research project
Structural and molecular mechanisms of the 55LCC ATPase complex and its function in DNA replication
- Start date: 1 September 2024
- End date: 31 August 2027
- Funder: Biotechnology and Biological Sciences Research Council (BBSRC)
- Value: 420,170.19
- Primary investigator: Dr Martina Foglizzo
Project title
Structural and molecular mechanisms of the 55LCC ATPase complex and its function in DNA replication
Description
DNA replication is essential for life because it helps to pass on genetic material from one generation to the next.
It’s also one of the first steps that cells must do to divide and create new cells – a process which happens nearly two trillion times a day.
Whilst DNA replication exercise is one of the most important processes in all living organisms, it’s also fraught with risks of mutation, which can lead to cell death or cancer.
In 2024, Dr Foglizzo was part of an international group of scientists that discovered a key quality-control mechanism in DNA replication called 55LCC.
55LCC works by utilising a small molecule called adenosine triphosphate (ATP), as an energy source to promote the disassembly of proteins involved in the replication of DNA when these are no longer required.
In doing so, 55LCC helps to govern the pausing or stopping of DNA replication to ensure its smooth progress.
Mutations in the proteins that help make up 55LCC are known to be associated with childhood syndromes involving hearing loss, cognitive and movement impairment, and epilepsy.
Research overview
The project aims to understand the molecular and mechanistic underpinnings of how 55LCC complex assembly directs substrate recruitment and regulates 55LCC enzymatic function.
It will address three main questions:
1) How do SPATA5 and SPATA5L1 contribute to 55LCC enzymatic activities?
2) What are the structural determinants and conformational dynamics of SPATA5 and 55LCC?
3) How does 55LCC associate with its substrates?
To answer these questions, Dr Foglizzo will combine structural, biochemical, biophysical and computational methods to gain insights into the determinants underpinning SPATA5 and 55LCC assemblies, and clarify the contributions SPATA5 and SPATA5L1 provide to 55LCC structure and function.
She will also use these approaches to quantitatively characterise 55LCC interaction with its biological substrates, and generate critical mechanistic information on how substrate recognition and processing is regulated by 55LCC.