SMARCAL1 is an ATP-dependent DNA translocase that plays a critical role in maintaining genome stability during DNA replication stress 1. The protein functions as an annealing helicase that catalyzes the rewinding of stably unwound DNA and binds selectively to fork DNA structures 1. SMARCAL1 participates in replication fork reversal, a mechanism that helps cells tolerate replication stress by reannealing parental template DNA strands 1. The protein exhibits profound synthetic lethality with FANCM, another DNA translocase, with their combined loss causing severe genome instability and chromosome 2 at loci enriched in simple repeats 2. SMARCAL1 also directly unwinds TA-rich DNA cruciforms, preventing catastrophic chromosome 2 3. Additionally, SMARCAL1 has specialized functions at telomeres, where it limits DNA damage during replication of difficult-to-replicate telomere sequences, with deficient cells displaying extrachromosomal telomere circles and DNA damage markers 4. Clinically, SMARCAL1 mutations cause Schimke immuno-osseous dysplasia and have been identified as causative mutations in steroid-resistant nephrotic syndrome 5. The protein's regulation is crucial, as RAD52 can restrict SMARCAL1-mediated fork reversal through competitive binding mechanisms 6.