Cancers can become dependent on DNA repair pathways when they lose specific DNA repair processes making them difficult to target. Now, scientists at the Francis Crick Institute report they have found a new way to prevent some tumors from repairing their own DNA.
Their findings are published in the journal Molecular Cell in a paper titled, “Defective ALC1 nucleosome remodeling confers PARPi sensitization and synthetic lethality with HRD.”
Using a mouse model, the researchers showed that blocking an enzyme called ALC1 in certain human cancer cells in the lab caused the cells to die.
“Chromatin is a barrier to efficient DNA repair, as it hinders access and processing of certain DNA lesions,” the researchers wrote. “ALC1/CHD1L is a nucleosome-remodeling enzyme that responds to DNA damage, but its precise function in DNA repair remains unknown. Here we report that loss of ALC1 confers sensitivity to PARP inhibitors, methyl-methanesulfonate, and uracil misincorporation, which reflects the need to remodel nucleosomes following base excision by DNA glycosylases but prior to handover to APEX1.”
The researchers decided to study ALC1, an enzyme due to its role in damaged DNA bases. To their surprise, the researchers observed cells lacking ALC1 were found to be sensitive to PARP inhibitor treatment.
“Using CRISPR screens, we establish that ALC1 loss is synthetic lethal with homologous recombination deficiency (HRD), which we attribute to chromosome instability caused by unrepaired DNA gaps at replication forks.”
HRD is harbored by approximately 13% and 15% of ovarian and triple-negative breast cancers (TNBC).
“This work provides strong evidence for developing new drugs that block the ALC1 enzyme. If shown to be effective in further studies, these drugs could be used alone or in combination with existing PARP inhibitors to target HRD cancers, explained Simon Boulton, PhD, senior author and group leader of the DSB Repair Metabolism Laboratory at the Crick.
The researchers also observed the genomes of human cancer cells where ALC1 had been removed. They observed that without this enzyme, DNA gaps accumulated in the cancer cells, which are normally repaired by HR.
“Not only have we shown that inhibiting ALC1 effectively leads to cancer cell death, but we have also found out the detailed mechanism behind this. Our increased understanding of this enzyme could help in the development of drugs which stop it working.”