TRAIP is an E3 ubiquitin ligase that functions as a critical guardian of genome stability during DNA replication stress 1. Its primary role involves regulating interstrand crosslink (ICL) repair by mediating ubiquitination of the MCG helicase complex, controlling pathway choice between nucleotide excision repair and Fanconi anemia-dependent mechanisms 2. TRAIP also facilitates DNA-protein crosslink repair through proteasomal degradation pathways 1. In mitosis, TRAIP triggers disassembly of stalled replisomes, preventing chromosome 3 and premature cell death—functions particularly critical for neural progenitor maintenance 3. Beyond DNA repair, TRAIP negatively regulates innate immune signaling by promoting ubiquitin-mediated degradation of signaling intermediates, thereby inhibiting NF-κB and interferon responses 4. Recent studies reveal TRAIP suppresses cancer progression through MYC degradation via K48-linked polyubiquitination 5. Dysregulation of TRAIP activity is tightly controlled by deubiquitylase USP37 to prevent inappropriate replisome disassembly 6. Mutations in TRAIP cause Seckel syndrome 9, a microcephalic primordial dwarfism characterized by defective neurogenesis 3. TRAIP variants affect cellular fitness under DNA damage stress, with distinct functional domains modulating topoisomerase poison sensitivity 7.