We elucidated the role of DNMT3B and its isoforms in DNA methylation by using the 3BKO and DKO8 derivatives of the HCT116 colon cancer cell line that have homozygous deletions for DNMT3B. DKO8 cells additionally have a markedly reduced protein level of a hypomorphic DNMT1 (DNMT1ΔE2-5) (refs 29, 30) allele. Here, DNMT3B is linked to colonic neoplasm.