Research led by the Francis Crick Institute has tracked down an
elusive enzyme that is key to repairing a type of DNA damage in
animals.
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 are particularly detrimental because they can block
cellular functions such as DNA replication and transcription, which
are essential to life.
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).
Confirming their results, the scientists showed that
inactivating SPRTN meant DPCs were not repaired and cells became
hypersensitive to the things that cause this type of DNA
damage.
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."
The paper, Mechanism and Regulation of DNA-Protein Crosslink
Repair by the DNA-Dependent Metalloprotease SPRTN, is published inMolecular Cell.