Cisplatin in the era of PARP inhibitors and immunotherapy.

Platinum compounds such as cisplatin, carboplatin and oxaliplatin are widely used in chemotherapy. Cisplatin induces cytotoxic DNA damage that blocks DNA replication and gene transcription, leading to arrest of cell proliferation. Although platinum therapy alone is effective against many tumors, cancer cells can adapt to the treatment and gain resistance. The mechanisms for cisplatin resistance are complex, including low DNA damage formation, high DNA repair capacity, changes in apoptosis signaling pathways, rewired cell metabolisms, and others. Drug resistance compromises the clinical efficacy and calls for new strategies by combining cisplatin with other therapies. Exciting progress in cancer treatment, particularly development of poly (ADP-ribose) polymerase (PARP) inhibitors and immune checkpoint inhibitors, opened a new chapter to combine cisplatin with these new cancer therapies. In this Review, we discuss how platinum synergizes with PARP inhibitors and immunotherapy to bring new hope to cancer patients.

High UV damage and low repair, but not cytosine deamination, stimulate mutation hotspots at ETS binding sites in melanoma.

Noncoding mutation hotspots have been identified in melanoma and many of them occur at the binding sites of E26 transformation-specific (ETS) proteins; however, their formation mechanism and functional impacts are not fully understood. Here, we used UV (Ultraviolet) damage sequencing data and analyzed cyclobutane pyrimidine dimer (CPD) formation, DNA repair, and CPD deamination in human cells at single-nucleotide resolution. Our data show prominent CPD hotspots immediately after UV irradiation at ETS binding sites, particularly at sites with a conserved TTCCGG motif, which correlate with mutation hotspots identified in cutaneous melanoma. Additionally, CPDs are repaired slower at ETS binding sites than in flanking DNA. Cytosine deamination in CPDs to uracil is suggested as an important step for UV mutagenesis. However, we found that CPD deamination is significantly suppressed at ETS binding sites, particularly for the CPD hotspot on the 5' side of the ETS motif, arguing against a role for CPD deamination in promoting ETS-associated UV mutations. Finally, we analyzed a subset of frequently mutated promoters, including the ribosomal protein genes RPL13A and RPS20, and found that mutations in the ETS motif can significantly reduce the promoter activity. Thus, our data identify high UV damage and low repair, but not CPD deamination, as the main mechanism for ETS-associated mutations in melanoma and uncover important roles of often-overlooked mutation hotspots in perturbing gene transcription.