Investigating recruitment and activity of the BRCA1-A complex on chromatin

Our DNA is constantly exposed to damage from natural processes inside the cell as well as from environmental factors such as radiation and chemicals. Cells rely on intricate molecular systems to repair this damage and prevent the harmful mutations that can lead to cancer. One of the most important of these systems is controlled by BRCA1, a tumour suppressor protein frequently mutated in breast and ovarian cancer.
BRCA1 does not act alone. It functions within large molecular machines, including the BRCA1-A complex, which helps to control how DNA double-strand breaks are detected and repaired. This complex is thought to prevent inappropriate processing of broken DNA ends, ensuring that repair happens in a controlled way. However, many fundamental questions remain unanswered. We do not fully understand how the BRCA1-A complex assembles, how it is recruited to damaged DNA, how its component enzymes cooperate or compete, and how the repair process is switched off once the DNA is restored. These gaps in knowledge are critical, as failure to regulate these steps contributes to cancer development and treatment resistance.
Our project will directly address these questions. Using structural biology, chemical biology, biochemistry and cell biology, we will study how BRCA1-A recognises the molecular “tags” placed on DNA and chromatin during damage. These tags include chains of ubiquitin and SUMO, which act like signals to recruit and regulate repair factors. We will investigate how BRCA1-A binds and processes these signals, how its subunits assemble into a functional supercomplex, and how its two opposing enzyme activities — one that removes ubiquitin chains and one that adds them — are coordinated. Importantly, we will reconstitute the entire 1.5 MDa BRCA1-A complex with defined, site-specifically modified chromatin substrates. This has never been achieved before and represents a major technical advance.
Our team brings together complementary expertise: structural biology of...