BRCA1 is one of the best-known genes linked to breast cancer risk. Mutations in the BRCA1 gene were found in around 50% of familial breast cancer cases. The major BRCA1 binding partner, BARD1, is also implicated in the prognosis of breast cancer. Depletion of BARD1 renders DNA damage sensitivity, homologous recombination (HR) deficiency and genome destabilization. The ablation of BARD1 in mice leads to cancer susceptibility, and probable disease-causing mutations are found in patients with breast cancer. Deubiquitinase enzymes (DUBs) play critical roles in ubiquitin-directed signaling by catalytically removing the protein “tag” ubiquitin from substrates. In this study, scientists found that the deubiquitinase USP15 plays an important role in cancer cells’ response to PARP inhibitors. USP15 is a member of the largest subfamily of cysteine protease DUBs. It has been implicated in the biological effects of trasforming growth factor-β and one morphogenetic protein response, immune responses and neuro-inflammation. The Cancer Genome Atlas indicates that USP15 enzyme deletions occur in 16% of breast cancers and in 5% of pancreatic cancers.
Studies have shown that cancer-associated USP15 mutations increase poly ADP ribose polymerase (PARP) inhibitor sensitivity in cancer cells. PARP inhibitors are a new class of pharmacological inhibitors developed for multiple purposes, but chiefly for the treatment of cancer. They have garnered a great deal of attention for their potential in the management of patients with BRCA mutations. Researchers at the George Washington University (GW) Cancer Center found that the enzyme USP15 could potentially lead to new treatments for breast and pancreatic cancer. Their findings were published in Nature Communications. The team team found that USP15 regulates homologous recombination (HR) — one of the major pathways to repair DNA damage affecting broth strands of the double helix — and cancer cell response to PARP inhibitors. In mammalian cells, there are two prominent repair pathways that repair double strand breaks (DSBs): homologous recombination (HR) repair and non-homologous end-joining (NHEJ) mechanisms. NHEJ is referred to as “non-homologous” because the break ends are directly ligated without homologous templates.
So, NHEJ is commonly associated with the presence of insertions and deletions at DNA doubles strand breaks. HR is different from NHEJ, which needs an intact homologous template. USP15 is an enzyme responsible for removing ubiquitin chains from proteins and other molecules, which play important roles in maintaining genome stability. Based on their research, Pei and his team believe USP15 may function similarly to the USP4 and USP11 enzymes, which were found to play a role in DNA repair by Pei’s group four years ago and other research teams. Huadong Pei, PhD, assistant professor of Biochemistry and Molecular Medicine at the GW School of Medicine and Health Sciences and senior author on the study, summarized: “With this study, we validate the role of USP15 in maintaining genome stability and tumor suppression and inform novel treatments for breast cancer. With consistent research and progress of current studies, we will gain a stronger understanding and a more comprehensive view of USP15 functions in cancer and their role in future treatment strategies”.
As a next step, researchers will use patient-derived tissue graft models to examine the impact of the USP15 enzyme on radio-chemotherapy response. Additionally, they will perform high-throughput screening for USP15 inhibitors.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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