Speaker: Vicenzo Costano - IFOM
Date: Tuesday 14th January
Time: 12:00pm
Venue: Jean Thomas Lecture Theatre
Abstract:
"The maintenance of genomic stability is a cornerstone of cellular integrity, with homologous recombination (HR) proteins—such as RAD51, BRCA1, and BRCA2—playing pivotal roles in this process. While HR has traditionally been studied in the context of DNA double-strand break (DSB) repair, emerging evidence suggests a more expansive role for these proteins in the regulation and protection of DNA replication. Deficiencies in HR pathways result in the accumulation of mutations and genomic instability, which are hallmarks of cancer development. However, the precise mechanisms through which HR factors coordinate their dual roles in replication and repair remain incompletely understood.
Our studies have started to elucidate the molecular functions of HR proteins in replication fork stability and DNA damage suppression. Utilizing biochemical model systems, DNA electron microscopy, and replication fiber analysis, we have uncovered critical roles for RAD51 and BRCA2 in preventing the degradation of nascent DNA and limiting the accumulation of single-stranded (ss) DNA gaps (Hashimoto et al., NSMB 2010; Kolinjivadi et al., Mol Cell 2017). These findings offer new insights into the cellular strategies for safeguarding replication fork integrity.
Moreover, our work has demonstrated that POLθ, an alternative DNA polymerase, mitigates the replication stress caused by the loss of BRCA1, BRCA2, or RAD51 by suppressing ssDNA gap accumulation, thereby preventing replication fork collapse mediated by the MRE11 nuclease (Mann et al., Mol Cell 2022).
More recently, in collaboration with the Pellegrini laboratory in Cambridge, we have revealed a novel function of RAD51 in directly recognizing and binding to abasic sites, as confirmed by cryo-electron microscopy (Hanthi et al., Mol Cell 2024). This mechanism is critical for safeguarding replication forks by preventing the accumulation of ssDNA gaps triggered by abasic sites and preventing fork breakage induced by the MRE11 nuclease.
These findings represent significant progress in our understanding of how HR proteins function beyond their canonical roles, acting as guardians of the genome. I will discuss the implications of these observations for the broader fields of replication biology, DNA repair, and cancer therapeutics."