Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder that is caused by a point mutation in the LMNA gene, resulting in production of a truncated farnesylated-prelamin A protein (progerin).We previously reported that XPAmislocalized to the progerin-inducedDNAdouble-strand break (DSB) sites, blocking DSB repair, which led to DSB accumulation,DNA damage responses, and early replication arrest inHGPS. In this study, the XPA mislocalization to DSBs occurred at stalled or collapsed replication forks, concurrent with a significant loss of PCNA at the forks, whereas PCNA efficiently bound to progerin. This PCNA sequestration likely exposed ds-ssDNA junctions at replication forks for XPA binding. Depletion of XPA or progerin each significantly restored PCNAat replication forks.Our results suggest that although PCNAismuchmore competitive than XPAin binding replication forks, PCNA sequestration by progerin may shift the equilibrium to favor XPA binding. Furthermore, we demonstrated that progerin-induced apoptosis could be rescued by XPA, suggesting that XPAreplication fork binding may prevent apoptosis in HGPS cells. Our results propose a mechanism for progerininduced genome instability and accelerated replicative senescence in HGPS. - Hilton, B. A., Liu, J., Cartwright, B.M.,Liu,Y.,Breitman,M.,Wang,Y., Jones,R.,Tang, H.,Rusinol,A.,Musich,P.R.,Zou,Y.Progerin sequestrationof PCNApromotes replication fork collapse andmislocalization ofXPAin laminopathy-related progeroid syndromes.