Our data demonstrate that UHRF1-mediated XRCC4 upregulation occurs at the transcript level in retinoblastoma cells, and the enhanced XRCC4 expression reduces etoposide-induced apoptosis by ensuring efficient chromatin loading of DNA ligase IV for the end-joining activity required for the repair following the genotoxic insults. Here, UHRF1 is linked to retinoblastoma.