ZRANB3 is a DNA annealing helicase and endonuclease that maintains genome stability at stalled or collapsed replication forks 1. The protein is recruited to sites of stalled DNA replication by polyubiquitinated PCNA and functions as a structure-specific endonuclease that cleaves replication fork D-loop intermediates, generating accessible 3'-OH groups for DNA polymerase extension 1. ZRANB3 catalyzes fork regression through annealing helicase activity to prevent replication fork disintegration and double-strand break formation 1. The protein works alongside other SNF2 family ATPases like SMARCAL1 and HLTF in fork remodeling, with each having specialized non-redundant functions 2. ZRANB3 demonstrates efficient branch migration activity and motor-driven translocase functions that are stimulated by RAD51 and paralog complexes 2. In hematopoietic stem cells, ZRANB3 has essential cell-intrinsic functions protecting against replication stress and DNA damage, with deficiency leading to accelerated aging-related hematopoietic dysregulation 3. The protein's levels influence DNA damage tolerance pathway hierarchy, coordinating fork reversal with other replication stress responses 4. ZRANB3 mutations are linked to cancer, and interestingly, genetic variants show association with type 2 diabetes in African populations through effects on pancreatic β-cell mass and insulin response 5.