TY - JOUR
T1 - Spatial separation between replisome- and template-induced replication stress signaling
AU - García-Rodríguez, Néstor
AU - Morawska, Magdalena
AU - Wong, Ronald P.
AU - Daigaku, Yasukazu
AU - Ulrich, Helle D.
N1 - Funding Information:
We thank IMB’s Microscopy core facility for advice with fluorescence microscopy, IMB’s media laboratory for supplies, and John Diffley, Susan Gasser, Nicolas Hoch, Philippe Pasero, Félix Prado, Rodney Rothstein, Kristina Schmidt and Ralf Wellinger for providing reagents. This work was funded by Cancer Research UK and an Advanced Grant of the European Research Council (ERC AdG 323179: DAMAGE BYPASS).
Publisher Copyright:
© 2018 The Authors. Published under the terms of the CC BY 4.0 license
PY - 2018/5/2
Y1 - 2018/5/2
N2 - 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.
AB - 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.
KW - DNA damage bypass
KW - DNA damage checkpoint
KW - Exo1
KW - postreplication repair
KW - replication stress
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U2 - 10.15252/embj.201798369
DO - 10.15252/embj.201798369
M3 - Article
C2 - 29581097
AN - SCOPUS:85045977892
VL - 37
JO - EMBO Journal
JF - EMBO Journal
SN - 0261-4189
IS - 9
M1 - e98369
ER -