In the body, mutations can arise from DNA damage that is not repaired properly, leading to genome instability and cancer or neurodegenerative disease. Now a new study by the University of Sussex’s Genome Damage and Stability Centre has identified how the enzyme PARP3, full name poly(ADP-ribose) polymerase 3, recognises and signals the presence of broken DNA strands.
The enzyme, which is known to help with DNA repair, is one of a superfamily of PARP enzymes being targeted by PARP inhibitor drugs, a new class of drugs used to treat hereditary cancers, including ovarian and breast cancer.
Now scientists in the laboratories of Professors Keith Caldecott and Laurence Pearl at the University of Sussex have identified the nature and location of the molecular ‘signal’ created by PARP3 at damaged DNA; a chemical change known as ‘ADP-ribosylation’ which, when added to a specific chromatin subunit known as histone H2B, ‘marks' the DNA damage site.
The scientists believe the findings from the research, funded by Cancer Research UK and the Medical Research Council, are a vital step towards understanding how DNA breaks are detected, signalled and repaired, which in the future will enable scientists to create drugs which better target specific cancers.
Professor Keith Caldecott, from the University of Sussex, said:
“This discovery highlights the value of multi-disciplinary collaborations, combining molecular and cellular biology with biochemistry and structural biology. As a result of working together, we have been able to identify how PARP3 recognises and flags the presence of broken DNA.
“This will be important for our understanding of how cells protect themselves from potentially dangerous DNA breaks. It will also help to provide insight into the mechanisms of a new class of PARP inhibitory anti-cancer drugs.”
The research also involved nuclear magnetic resonance expertise in the Matthews group at Imperial College London, proteomics in the lab of Steve Sweet at the University of Sussex and chromatin biology in the laboratory of Alan Thorne at the University of Portsmouth.
The study, entitled “PARP3 is a sensor of nicked nucleosomes and monoribosylates histone H2BGlu2”, has been published in Nature Communications and can be found here.