Abstract

Lamin A/C is essential for maintaining nuclear architecture, organizing chromatin, and preserving genomic stability. However, its role in regulating DNA replication remains unclear. This study investigates how lamin A/C regulates proper replication initiation by orchestrating the chromatin structure and the recruitment of proliferating cell nuclear antigen (PCNA). We demonstrate that lamin A/C deficiency leads to an increase in chromatin dynamics, replication domain (RD) accessibility, and PCNA availability at RDs, which together facilitate increased initiation density and replication-dependent DNA damage. These disruptions prolong the S phase and compromise genome stability, highlighting lamin A/C as a critical gatekeeper of balanced replication initiation. Our findings reveal lamin A/C’s dual role in chromatin structure organization and replication machinery regulation, offering valuable insights into its involvement in replication-associated diseases and potential therapeutic opportunities.