PHRF1 (PHD and Ring Finger Domains 1) is a multifunctional E3 ubiquitin ligase and histone reader that plays critical roles in DNA damage response and genome stability. Structurally, PHRF1 contains a plant homeodomain (PHD) that recognizes methylated histones, particularly histone H3 at its N-terminal region and H3K36me2/me3 12, and a RING domain conferring E3 ligase activity. Primary functions include: (1) ATR pathway activation through mono-ubiquitination of TopBP1 at lysine 73, enhancing TopBP1-ATR signaling during replication stress 3; (2) promotion of non-homologous end-joining (NHEJ) through H3K36 methylation recognition and NBS1 binding 2; and (3) p53 regulation via ubiquitin-proteasome degradation, particularly under cisplatin-induced DNA damage 4. Beyond DNA repair, PHRF1 modulates transcription through RNA polymerase II interaction 56, regulating invasion-associated genes including ZEB1 and SOX4 in lung and colorectal cancers respectively. Disease relevance: PHRF1 acts as a tumor suppressor, with reduced expression in lung cancer 7. Cancer-associated mutations in the PHD finger abolish histone binding and impair DNA damage response 1. PHRF1 genetic variants associate with hyperhemolysis syndrome in sickle cell disease 8. PHRF1 knockout mice exhibit early lethality and impaired ATR-Chk1 signaling, highlighting its essential role in genomic stability 3.