HLTF

Functions as a DNA-dependent ATPase and E3 ubiquitin-protein ligase involved in chromatin regulation and DNA damage tolerance (DDT). Catalyzes 'Lys-63'-linked polyubiquitination of monoubiquitinated PCNA at 'Lys-164' in response to genotoxic stress, promoting error-free postreplication repair via template switching. Acts as an epigenetic regulator by promoting recruitment of DNMT1, thereby ensuring DNA methylation inheritance: specifically binds histone H3 trimethylated at 'Lys-9' (H3K9me3) and mediates histone H3 'Lys-23' polyubiquitination (H3K23ub), a docking site for DNMT1, leading to DNMT1 recruitment and replication-coupled DNA methylation maintenance. Catalyzes formation of H3K23ub in two steps: first mediates monoubiquitination together with UBE2E1 and UBE2D2, and then extends ubiquitin chains via 'Lys-63'-linked ubiquitination together with UBE2N and UBE2V2. Also acts as a chromatin redodeling factor, thereby regulating transcription. Exhibits ATP-dependent double-stranded DNA (dsDNA) translocase activity but lacks classical helicase activity; mediates replication fork reversal by concertedly unwinding and annealing nascent and parental strands, thereby suppressing DNA synthesis and maintaining genomic stability. Resolves G-quadruplex (G4) DNA structures in cooperation with MSH2, limiting replication stress and G4 accumulation across the cell cycle. Contributes to nucleotide excision repair by evicting lesion-containing oligonucleotides using its HIRAN and ATPase domains. Can displace single-stranded DNA from triplex structures through ATP-dependent dsDNA translocation. Also has protein clearing activity at the stalled replication fork, facilitating restart of DNA replication..

Function from UniProtKB (Q14527), read 2026-09-23. CC BY 4.0.