LAP2α preserves genome integrity through assisting RPA deposition on damaged chromatin

BACKGROUND: Single-stranded DNA (ssDNA) coated with replication protein A (RPA) acts as a key platform for the recruitment and exchange of genome maintenance factors in DNA damage response. Yet, how the formation of the ssDNA-RPA intermediate is regulated remains elusive. RESULTS: Here, we report that the lamin-associated protein LAP2α is physically associated with RPA, and LAP2α preferentially facilitates RPA deposition on damaged chromatin via physical contacts between LAP2α and RPA1. Importantly, LAP2α-promoted RPA binding to ssDNA plays a critical role in protection of replication forks, activation of ATR, and repair of damaged DNA. We further demonstrate that the preference of LAP2α-promoted RPA loading on damaged chromatin depends on poly ADP-ribose polymerase PARP1, but not poly(ADP-ribosyl)ation. CONCLUSIONS: Our study provides mechanistic insight into RPA deposition in response to DNA damage and reveals a genome protection role of LAP2α. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13059-022-02638-6.