Publication highlights

Researchers at the Crick have used cryo-EM to unveil the structure of an assembled retrovirus, called Prototype Foamy Virus (PFV), revealing the structure and function of the virus' surface proteins and internal capsid. The surface protein which is used in entering host cells was found to be similar to proteins on the surface of parainfluenza viruses and coronaviruses, an unexpected relationship. PFV is a promising vector system for gene therapy and cancer treatment.

The human RAD52 protein plays an important role in several cellular processes, including the repair of chromosome breaks and the maintenance of telomere length (structures at the end of chromosomes) to avoid cellular aging. During DNA repair, it provides an alternative to the BRCA2 protein, which is mutated in many inheritable breast, ovarian and prostate cancers. Consequently, targeting RAD52 could be used to kill tumours with BRCA2 mutations, where growth is uncontrolled. To elucidate the mechanism of repair by RAD52, we determined the atomic structure of the protein using cryo-electron microscopy, and found that the protein forms a ring in which the broken DNA wraps around the outside of the ring. Having the atomic structure gives us new insights into ways to identify small molecules that can be used to inhibit repair by RAD52 and kill BRCA2-defective tumours.

Individuals with inheritable mutations in the BRCA1 or BRCA2 tumour suppressor genes are unable to carry out a DNA repair process known as homologous recombination, and are predisposed to breast, ovarian and prostate cancers. In the clinic, these cancers are treated with inhibitors of poly [ADP-ribose] polymerase (PARPi) which knocks out a second repair process, and makes the tumour cells die. While effective at initial cancer maintenance, after a period of time the tumours unfortunately develop resistance to PARP inhibition leading to further growth. However, researchers recently discovered that loss or inhibition of a nucleotide pool sanitiser called DNPH1 sensitises BRCA-deficient cells to PARPi, offering a promising strategy for improved therapy for these individuals. The DNPH1 normally removes faulty nucleotides from the cell to stop their incorporation into DNA, so DNPH1 loss leads to an overload in the second repair pathway that is sensitive to PARPi, causing tumour cell death. There is now significant pharmaceutical interest in the development of small molecules that will target and inhibit DNPH1. Towards this goal researchers at the Crick have determined the X-ray crystal structure of DNPH1 bound to the molecule that it acts upon, which will now allow rational drug design.

Research from Ian Taylor’s lab has investigated the molecular basis of Ty1 transposition, which is regulated by copy number control. Their work presents the structural, biophysical and genetic analyses of p18m, a key protein that directs copy number control through disruption of Ty1 virus-like particle assembly.