RECQL5 is a 3'-5' DNA helicase 1 that functions as a multifaceted genome maintenance enzyme operating at the intersection of DNA replication, transcription, and repair 2. Mechanistically, RECQL5 binds to elongating RNA polymerase II and suppresses transcription-associated genomic instability by slowing transcription elongation 3, while also associating with POLR1A to stabilize ribosomal DNA 4. During replication stress, RECQL5 removes RAD51 filaments from stalled forks and stimulates MUS81-EME1 nuclease activity to promote mitotic DNA synthesis 5. The helicase facilitates DNA repair including inter-strand cross-link resolution 6 and prevents sister chr17 exchange and homologous recombination 2. Disease relevance is substantial: Recql5-deficient mice develop cancer with increased chr17 instability 2, and human RECQL5 upregulation correlates with poor prognosis in lung adenocarcinoma and promotes cisplatin resistance 7. Genetic polymorphisms in RECQL5 associate with laryngeal cancer and osteosarcoma risk in Chinese populations 89. Unlike other RecQ family members, RECQL5 has not been definitively linked to Mendelian syndrome, though its dysregulation clearly contributes to cancer development and therapeutic resistance 10.