Enzyme USP15 regulates DNA homologous recombination repair and cancer cells response to PARP inhibitors

Researchers at George Washington University's (GW) cancer center have found that the enzyme USP15 may lead to new treatments for breast and pancreatic cancer. Their findings are published in Nature Communications.

Though this study, they validated the role of USP15 in maintaining genomic stability and tumor suppression and provided information for new therapies for breast cancer. And they will have a deeper understanding and a more comprehensive view of the role of USP15 in cancer and its role in future treatment strategies.

USP15 deletion occurs in 16% of breast cancers and 5% of pancreatic cancers, according to the cancer genome map. Studies have shown that cancer-related USP15 mutations increase the sensitivity of poly adenosine diphosphate ribose polymerase (PARP) inhibitors in cancer cells.

PARP is a DNA repair enzyme that plays a key role in the DNA repair pathway. When DNA damage is broken, PARP is activated. As a molecular receptor for DNA damage, it recognizes and binds to the location of DNA breaks, thereby activating and catalyzing the poly ADP ribosylation of receptor proteins and participating in the DNA repair process.

PARP inhibitors are a new class of drug inhibitors that are primarily used to treat cancer. PARP inhibitors can enhance the efficacy of radiotherapy and alkylating agents and platinum-based chemotherapy by inhibiting the repair of DNA damage in tumor cells and promoting apoptosis of tumor cells. Their potential in managing patients with BRCA mutations has received a great deal of attention.

BRCA1 and BRCA2 are human genes producing tumor suppressor proteins. These proteins help repair damaged DNA. When any of these genes are mutated or altered, resulting in the inability of the protein product to act or function properly, DNA damage may not be properly repaired. Therefore, cells are more likely to produce additional genetic alterations that lead to cancer.

The particular genetic mutations in BRCA1 and BRCA2 are most pronounced in women with increased risk of breast and ovarian cancer, but they are also associated with an increased risk of several other cancers. Human BRCA1 and BRCA2, which are genetically inherited, tend to develop breast and ovarian cancer at a younger age than those without these mutations.

The team found that USP15 regulates DNA homologous recombination repair and cancer cells response to PARP inhibitors.

There are many types of DNA damage, among which the double-strand break (DSB) is the most serious. The repair of DNA DSB is more difficult than other types of DNA damage. If it is not repaired, it may result in chromosome breakage and cell death. Improper repair may cause chromosome deletion, rearrangement, translocation, and inversion, etc., which is easy to form tumors and other diseases.

Incomplete repair of DNA damage also can lead to genomic instability. In order to combat damage, the body cells develop multiple repair systems to ensure the integrity of the genome. Homologous recombination repair (HRR) is the main way to repair DNA DSB damage. It is important to maintain the genomic integrity of mammalian cells.

USP15 is part of a group of deubiquitination enzymes responsible for removing the ubiquitin chains from proteins and other molecules that play important roles in maintaining genomic stability. Based on their research, the team believed that USP15 may be similar to the USP4 enzyme, which was discovered by the research team four years ago in DNA repair.

USP15 is a potential biomarker for the treatment of pancreatic cancer as well as breast and ovarian cancer.

Next, the researchers will examine the effects of USP15 on chemoradiotherapy using a tissue transplant model derived from a patient. In addition, they will perform high-throughput screening of USP15 inhibitors.