RAD54L2 is an ATP-dependent DNA/RNA helicase that regulates transcription and genome stability through multiple mechanisms. In transcriptional regulation, RAD54L2 modulates androgen receptor-dependent transactivation by stimulating RNA polymerase II release from paused transcription start sites and unwinding R-loops at these sites 1. The helicase also facilitates double-strand break formation by TOP2B, which appears important for transcriptional output 1. Beyond transcription, RAD54L2 counters topoisomerase 2 (TOP2)-DNA adducts through a novel mechanism involving sumoylated TOP2 recognition and ATPase activity, promoting TOP2 cleavage complex resolution and preventing double-strand break exposure 2. RAD54L2 participates in the TRAF3-DYRK1A-RAD54L2 complex to regulate ACE2 expression, affecting SARS-CoV-2 cellular entry 3. Disease relevance includes cancer associations: RAD54L2 downregulation occurs in renal cell carcinoma, correlating with poor survival outcomes 4; circular RAD54L2 promotes triple-negative breast cancer progression via the miR-888/PDK1 axis 5; and RAD54L2 genetic variants influence lung cancer susceptibility 6. RAD54L2 modulates response to etoposide chemotherapy in pediatric AML 7 and is classified among homologous recombination repair genes affecting PARP inhibitor response in prostate cancer 8.