DNA is wrapped around proteins called histones, which help to squeeze the long strands of DNA into the cell nucleus. When a double-strand DNA break occurs, the histones at each end of the DNA break are modified. This involves 'labeling' the break by coupling a protein called ubiquitin (a process known as ubiquitination) to the histones, which directs the various molecules required for DNA repair to the broken portion of DNA. Dr. Citterio's work has shown that the timely removal of ubiquitin ('deubiquitination') by a specific protein called 'human ubiquitin-specific protease 3' is very important for efficient repair of the DNA breaks. By promoting DNA repair, ubiquitin-specific protease 3 helps to prevent the accumulation of multiple DNA breaks in human cells and to reduce the risk of cancer.
Two main processes are available to mend double-strand DNA breaks: The first is directly joining the ends back together without any processing (non-homologous end-joining). The second is repairing the break by copying the information from an intact matching DNA molecule, in an approach that relies on extensive processing of the DNA ends (homologous recombination). These two mechanisms cannot be used interchangeably to repair double-strand DNA breaks, because breaks need to be repaired by a specific process according to the cellular context.
Dr. Di Virgilio and her team investigate how the repair pathway is chosen for double-strand DNA breaks. The key regulator of this process is a protein called 53BP1. 53BP1 is a DNA repair factor that marks the loose ends of broken DNA. Protection of the DNA ends by 53BP1 ensures that the DNA is repaired by non-homologous end-joining. In situations where cells have to use the homologous recombination type of repair, the DNA repair protein BRCA1 displaces 53BP1 to allow this alternative repair process to take place.
This process goes awry in cells that do not have a working copy of the BRCA1 gene, which is frequently mutated in hereditary breast and ovarian cancers. As a result, DNA double-strand breaks that should be mended by homologous recombination are instead fixed with non-homologous end-joining, causing genomic instability and predisposing the cell to carcinogenesis. Dr. Di Virgilio's research has shown that 53BP1 needs to be phosphorylated first before it can recruit factors that protect the DNA ends such as the DNA damage response proteins Rif1 and PTIP, which in turn are key factors in promoting genome instability in BRCA1-deficient cells.
Dr. Jacobs and her team combine functional genetics with a method for inducible and reversible telomere deprotection to search for factors that act in DNA damage responses at telomeres. They have found that a protein called MAD2L2 localises deprotected telomeres and promotes fusion of chromosome ends by non-homologous end-joining, causing genomic instability. MAD2L2 also accumulates at DNA double-strand breaks caused by radiation and promotes end-joining of these breaks.
Another of Prof. Sotillo's studies looked at when the gene Mad2 was overexpressed at the same time as the cancer-causing gene Kras in the lung or in the breast of animals. These animals could initially be cured of cancer by therapies that prevented the activity of Kras, but would then relapse even though Kras had been inhibited. This finding suggests that the aneuploidy induced by Mad2 during tumour progression allows the cancer to evade therapies that target Kras. Prof Sotillo's hypothesis is that chromosome instability might produce more genetic diversity within cancer cells or enhance the rate of mutations, which could allow cancer cells to acquire harmful genetic changes that cannot be stopped by the usual DNA repair pathways.
By understanding how our cells repair the dangerous faults in our genes, both correctly and incorrectly, these researchers hope to identify pathways and molecules that can be targeted by drugs. The end goal is to develop novel treatments that ensure that cells with faulty DNA are fixed properly or stop dividing, so there is no risk they may cause cancer. For cancer that has already developed, these researchers hope to identify ways to improve the effectiveness of treatments that act by damaging the cancer cells' DNA.