Spatial separation between replisome‐ and template‐induced replication stress signaling

• Néstor García‐Rodríguez ^[1] ; Magdalena Morawska ^[1] ; Ronald P Wong ^[1] ; Yasukazu Daigaku ^[2] ; Helle D Ulrich ^[1]
  1. [1] Institute of Molecular Biology

     Institute of Molecular Biology

     Kreisfreie Stadt Mainz, Alemania

     
  2. [2] 2 Cancer Research UK London Research Institute Clare Hall Laboratories Blanche Lane South Mimms UK; 4Present address: Frontier Research Institute for Interdisciplinary Sciences Tohoku University Aoba‐ku Sendai Japan
• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 37, Nº. 9, 2018
• Idioma: inglés
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• Resumen

  • Polymerase‐blocking DNA lesions are thought to elicit a checkpoint response via accumulation of single‐stranded DNA at stalled replication forks. However, as an alternative to persistent fork stalling, re‐priming downstream of lesions can give rise to daughter‐strand gaps behind replication forks. We show here that the processing of such structures by an exonuclease, Exo1, is required for timely checkpoint activation, which in turn prevents further gap erosion in S phase. This Rad9‐dependent mechanism of damage signaling is distinct from the Mrc1‐dependent, fork‐associated response to replication stress induced by conditions such as nucleotide depletion or replisome‐inherent problems, but reminiscent of replication‐independent checkpoint activation by single‐stranded DNA. Our results indicate that while replisome stalling triggers a checkpoint response directly at the stalled replication fork, the response to replication stress elicited by polymerase‐blocking lesions mainly emanates from Exo1‐processed, postreplicative daughter‐strand gaps, thus offering a mechanistic explanation for the dichotomy between replisome‐ versus template‐induced checkpoint signaling.