HLTF (helicase-like transcription factor) is a multifunctional DNA-dependent ATPase and E3 ubiquitin-protein ligase that maintains genome stability through several mechanisms. As an ATP-dependent dsDNA translocase (lacking classical helicase activity), HLTF catalyzes replication fork reversal by unwinding and reannealing nascent and parental DNA strands, facilitating error-free postreplication repair via template switching 1. HLTF catalyzes Lys-63-linked polyubiquitination of monoubiquitinated PCNA at Lys-164 in response to genotoxic stress. Additionally, HLTF resolves G-quadruplex structures in cooperation with MSH2, suppressing G4 accumulation and replication stress while restraining DNA synthesis when G4s are stabilized 2. HLTF contributes to nucleotide excision repair and interacts with mismatch repair proteins MSH2 3. In disease contexts, excessive HLTF accumulation at stalled replication forks promotes MRE11-dependent fork degradation; the deubiquitinase USP37 counteracts HLTF to protect fork stability and promote BRCA1-deficient cell survival, making HLTF relevant to PARP inhibitor resistance 4. In glioblastoma, HLTF stabilization via the LINC01088/USP7 axis prevents ferroptosis and promotes malignancy 5. HLTF also functions in double-strand break repair outcomes 6 and serves as a context-dependent repressor of prime editing efficiency 7.