Asymmetry of DNA replication fork progression in Werner's syndrome.
Human aging is associated with accumulation of cells that have undergone replicative senescence. The rare premature aging Werner's syndrome (WS) provides a phenocopy of normal human aging and WS patient cells recapitulate the aging phenotype in culture as they rapidly lose the ability to proliferate or replicate their DNA. WS is associated with loss of functional WRN protein. Although the biochemical properties of WRN protein, which possesses both helicase and exonuclease activities, suggest an involvement in DNA metabolism, its action in cells is not clear. Here, we provide experimental evidence for a role of the WRN protein in DNA replication in normally proliferating cells. Most importantly, we demonstrate that in the absence of functional WRN protein, replication forks from origins of bidirectional replication fail to progress normally, resulting in marked asymmetry of bidirectional forks. We propose that WRN acts in normal DNA replication to prevent collapse of replication forks or to resolve DNA junctions at stalled replication forks, and that loss of this capacity may be a contributory factor in premature aging.
Rodríguez-López
Ana M
AM
Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
Jackson
Dean A
DA
Iborra
Francisco
F
Cox
Lynne S
LS
D000293:Adolescent; D000328:Adult; D000375:Aging / Q000235:genetics*; D002455:Cell Division / Q000235:genetics*; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics*; D004247:DNA / Q000235:genetics* / Q000378:metabolism; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism*; D004261:DNA Replication / Q000235:genetics*; D005090:Exodeoxyribonucleases; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008854:Microscopy, Electron; D053484:RecQ Helicases; D016196:S Phase / Q000235:genetics; D014898:Werner Syndrome / Q000235:genetics*; D000071657:Werner Syndrome Helicase
D004247:DNA; D005090:Exodeoxyribonucleases; D004265:DNA Helicases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase