LAP2α drives breast tumorigenesis by mitigating replication stress.

Replication protein A (RPA) plays a vital role in replication stress response, with RPA-coated single-stranded DNA (ssDNA) acting as a critical platform for the coordination of the genome surveillance machinery. In previous studies, we reported that the lamin-associated protein LAP2α interacts physically with RPA, aiding its localization to damaged chromatin for genome protection. However, the significance of the LAP2α-mediated RPA deposition in tumor progression remains unclear. Here, we reveal that LAP2α promotes breast tumorigenesis by counteracting replication stress-induced DNA damage. Furthermore, we demonstrate that defects in RPA loading caused by LAP2α deficiency slow breast tumor growth and sensitize tumors to chemotherapeutic treatments. In addition, we found that LAP2α could directly stimulate the loading of RPA onto ssDNA. Collectively, our study characterizes a critical role of LAP2α-enhanced RPA loading in promoting breast tumorigenesis and positions the LAP2α-RPA complex as a promising target for therapeutic intervention in breast cancer.