Abstract:

Cellular responses to DNA double strand breaks (DSBs) are dependent on a set of nucleosome “signposts” that are written, read and erased by highly specialised multi-protein complexes. The tumour suppressor and E3 ubiquitin ligase BRCA1-BARD1 is recruited to damaged chromatin via recognition of ubiquitylated Lys13/Lys15 on histone H2A and unmethylated Lys20 on H4. Interactions of BRCA1-BARD1 with the nucleosome surface promotes the covalent attachment of ubiquitin to Lys125/Lys127/Lys129 on H2A, thus ensuring a timely DNA repair. I will discuss our latest work (and that of others) using recombinant expression systems alongside with biochemical/biophysical and structural techniques that shed light into how the BRCA1-BARD1 complex recognises and modifies chromatin, and how its DNA repair and enzymatic activities are regulated.

In a parallel work, we identified a new ATPase complex (termed 55LCC) that directs replisome proteostasis to ensure genome integrity. I will describe the cryo-electron microscopy structure of 55LCC, which reveals a new molecular architecture and heterohexameric ATPase motor. Our findings define 55LCC-mediated proteostasis as critical for replisome quality control and genome stability, and provide a framework to understand pathogenic variants seen in human neurodevelopmental disorders.

Bio:

Martina Foglizzo is a Postdoctoral Fellow in the laboratory of Prof. Elton Zeqiraj at the University of Leeds. She completed her PhD and a short Postdoctoral training with Prof. Catherine Day and Assoc. Prof. Peter Mace at the University of Otago (New Zealand), where she studied the structure and function of ubiquitin E3 ligases and deubiquitylating enzyme complexes. Martina’s research interests are focused on understanding how ubiquitin signalling and chromatin post-translational marks regulate DNA repair, as well as how ATP-dependent macromolecular motors modulate DNA replication and ensure genome stability.