Our data supports a model in which UHRF1-dependent H3 ubiquitination ‘bookmarks’ genomic regions of low CpG density in late replicating chromatin for re-methylation by DNMT1, and that a disrupted UHRF1-DNMT1 ubiquitin signaling axis contributes to DNA hypomethylation in cancer. The gene discussed is UHRF1; the disease is cancer.