There are all sorts of things that go wrong with DNA and, for many of these, the repair mechanisms are well understood. But until now the method of repairing a type of damage called covalent DNA-protein crosslinks (DPCs) was unknown.
DPCs can be caused by a number of external factors such as ionising radiation, UV light, certain metal ions and, importantly, by chemotherapy drugs that contain platinum such as cisplatin and its family. They can also be induced by reactive substances produced inside a cell such as formaldehyde or acetaldehyde.
Dr Julian Stingele, who carried out much of the work at the Crick, says: “Restoring the native DNA sequence and structure by damage-specific repair mechanisms is essential to ensuring the stability of the genome.”
In an effort to track down the unidentified mechanism for DPC repair, the Crick scientists combined many different scientific approaches. These included genetic techniques in worms, mice and human cells, several cellular and biochemical methods and structural research including x-ray crystallography.
The resulting wealth of cellular, biochemical and structural data meant the scientists were able to identify the key enzyme in DPC repair as a metalloprotease called SPRTN. The metalloprotease family of enzymes involve a metal (in this case probably zinc) to break bonds between amino acids in peptides (small protein chains).
Dr Simon Boulton, Group Leader at the Crick, says: “Our work suggests that interfering with DPC repair by inhibiting SPRTN may represent a potential therapeutic opportunity that could be exploited to make quickly-dividing cancer cells more sensitive to chemotherapy with platinum-containing drugs.”
He adds: “SPRTN is mutated in a condition called Ruijs-Aalfs syndrome that causes premature aging and early-onset of the most common type of liver cancer. Our work also provides a molecular explanation for how SPRTN deficiency causes Ruijs-Aalfs syndrome, indicating that failed DPC repair is to blame.”