A Nature Communications Biology study published by Bridge Project collaborators Jacqueline Lees (Koch InstituteI) and James DeCaprio (Dana-Farber Cancer Institute) uncovers previously unknown mechanisms underlying the sensitivity of Merkel cell carcinoma, a rare and aggressive neuroendocrine skin cancer, to PRMT5 inhibitors. They found that PRMT5 inhibitor sensitivity is not dependent on the activation of tumor-suppressor gene p53, as previously believed. They further showed that PRMT5 inhibition disrupts intron splicing and impairs ATR signaling with increased DNA damage, which may point the way to improving the efficacy of PRMT5 inhibitors and help clinicians identify patients who are more likely to respond to these therapies.