Constitutive ATR Signaling Enforces Domain-Wide Origin Synchrony
- 1Hebrew University of Jerusalem
Abstract
Eukaryotic DNA replication relies on organized spatial-temporal domains, yet how neighboring origins are coordinated at the single-molecule level remains unresolved. Combining single-molecule DNA combing with super-resolution microscopy, we demonstrate that during unperturbed early S-phase, adjacent replication origins across diverse vertebrate species fire synchronously as a coordinated unit. This domain-wide temporal harmony is continuously enforced by a baseline, constitutive ATR CHK1 signaling axis that restrains local CDK2 and CDC7 kinase activities. Strikingly, replication stress dismantles this coordination, shifting origin activation toward an asynchronous, replicon-autonomous mode. Mechanistically, stress-induced phosphorylation of the cohesin subunit SMC1A promotes an SMC1A ATR complex that sequesters ATR at stalled replication forks. This localized sequestration creates a regional ATR loss-of-function phenotype, relieving CDK2/CDC7 suppression and driving premature, uncoordinated origin firing. Super-resolution imaging shows that ATR sequestration structurally reorganizes replication foci, converting coordinated clustered foci into fragmented, lower-density clusters. Together, our findings uncover a baseline role for constitutive ATR signaling in enforcing domain synchrony and reveal a molecular switch that dynamically decouples origin activation during genomic stress to safeguard chromosome duplication.
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BibTeX
@misc{kamar2026constitutive,
title = {{Constitutive ATR Signaling Enforces Domain-Wide Origin Synchrony}},
author = {J. Kamar and S. Eden and S. K. Pradhan and M. K. Pabba and M. Arroyo and A. Greenberg and L. Daniel and M. C. Cardoso and I. Simon},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.19.760027},
url = {https://www.biorxiv.org/content/10.64898/2026.10.19.760027v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Constitutive ATR Signaling Enforces Domain-Wide Origin Synchrony
AU - J. Kamar
AU - S. Eden
AU - S. K. Pradhan
AU - M. K. Pabba
AU - M. Arroyo
AU - A. Greenberg
AU - L. Daniel
AU - M. C. Cardoso
AU - I. Simon
PY - 2026
DA - 2026/10/19
PB - bioRxiv
DO - 10.64898/2026.10.19.760027
UR - https://www.biorxiv.org/content/10.64898/2026.10.19.760027v1
AB - Eukaryotic DNA replication relies on organized spatial-temporal domains, yet how neighboring origins are coordinated at the single-molecule level remains unresolved. Combining single-molecule DNA combing with super-resolution microscopy, we demonstrate that during unperturbed early S-phase, adjacent replication origins across diverse vertebrate species fire synchronously as a coordinated unit. This domain-wide temporal harmony is continuously enforced by a baseline, constitutive ATR CHK1 signaling axis that restrains local CDK2 and CDC7 kinase activities. Strikingly, replication stress dismantles this coordination, shifting origin activation toward an asynchronous, replicon-autonomous mode. Mechanistically, stress-induced phosphorylation of the cohesin subunit SMC1A promotes an SMC1A ATR complex that sequesters ATR at stalled replication forks. This localized sequestration creates a regional ATR loss-of-function phenotype, relieving CDK2/CDC7 suppression and driving premature, uncoordinated origin firing. Super-resolution imaging shows that ATR sequestration structurally reorganizes replication foci, converting coordinated clustered foci into fragmented, lower-density clusters. Together, our findings uncover a baseline role for constitutive ATR signaling in enforcing domain synchrony and reveal a molecular switch that dynamically decouples origin activation during genomic stress to safeguard chromosome duplication.
ER -