LAP2α drives breast tumorigenesis by mitigating replication stress

TL;DR

This study shows that LAP2α helps breast tumors grow by reducing DNA damage during replication, and targeting LAP2α could be a new treatment approach.

Contribution

The novel contribution is the discovery that LAP2α promotes breast tumorigenesis by enhancing RPA loading on DNA.

Findings

LAP2α promotes breast tumorigenesis by counteracting replication stress-induced DNA damage.

LAP2α deficiency slows tumor growth and increases sensitivity to chemotherapy.

LAP2α directly stimulates RPA loading onto single-stranded DNA.

Abstract

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.

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