Progerin sequestration of PCNA promotes replication fork collapse and mislocalization of XPA in laminopathy-related progeroid syndromes

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
Benjamin A HiltonYue Zou

Abstract

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 XPA mislocalized to the progerin-induced DNA double-strand break (DSB) sites, blocking DSB repair, which led to DSB accumulation, DNA damage responses, and early replication arrest in HGPS. 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 PCNA at replication forks. Our results suggest that although PCNA is much more competitive than XPA in 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 XPA-replication fork binding may prevent apoptosis in HGPS cells. Our results propose a mechanism for progerin-induced genome instability and accelerated repl...Continue Reading

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Citations

Oct 21, 2017·The Journal of Cell Biology·Leonid Serebryannyy, Tom Misteli
Oct 5, 2019·Experimental Biology and Medicine·Muriel W Lambert
Dec 14, 2019·Proteomics·Nuria Coll-BonfillSusana Gonzalo
Jun 26, 2018·Nucleus·Romina BurlaIsabella Saggio
Apr 3, 2020·International Journal of Molecular Sciences·Lucia Borszéková PulzováMiroslav Chovanec
Jul 8, 2019·GeroScience·Susana Gonzalo, Nuria Coll-Bonfill
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Apr 26, 2019·International Journal of Molecular Sciences·Moritz MessnerMarc-Michael Zaruba
Nov 5, 2019·Frontiers in Genetics·Sára Sándor, Enikő Kubinyi
Dec 10, 2020·Médecine sciences : M/S·Paula FontanillaPascale Bertrand
May 1, 2021·Genes·Simon WillaumePascale Bertrand
Jul 3, 2021·International Journal of Molecular Sciences·Matthew GoelzerGunes Uzer

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