Replication stress links Geminin depletion to centrosome amplification
- 1California Institute of Technology
Abstract
The timing of DNA replication and centrosome duplication is tightly regulated with cell cycle progression to ensure the faithful duplication of the genome during cell division. Both DNA and centrosomes are licensed for replication in late telophase/early G1, replicated in S phase and segregated during mitosis; yet how defects in DNA replication licensing are coupled to centrosome homeostasis remains poorly understood. Here, we show that depletion of the replication licensing inhibitor Geminin in proliferating mouse embryonic fibroblasts induces robust centrosome amplification together with impaired primary cilium assembly. Rather than promoting whole-genome reduplication, knockdown of Geminin triggers a replication stress response, characterized by DNA damage accumulation throughout the cycle, and activation of an ATR-dependent DNA damage response. Mechanistically, Geminin depletion-induced replication stress activates the ATR-Chk1-Wee1 checkpoint axis prolonging G2 and leading to premature centriole disengagement and centrosome amplification. These findings identify replication stress as the signaling module that couples defective DNA replication licensing to centrosome amplification.
Related
- Lactate drives the emergence of tumor cells with centrosome amplification through CP110 lactylation
- Deoxynivalenol increases cell vulnerability to genotoxic stress through translational depletion of DNA damage response proteins
- Polymerase iota coordinates adaptation to replication stress in BRCA2-deficient mammary epithelial cells
- Perturbation of the replication stress-ATR axis accelerates human erythroid differentiation but blocks terminal maturation
- DNA replication stress redistributes the histone methyltransferase G9a and activates lineage-specific gene expression
BibTeX
@misc{santos2026replication,
title = {{Replication stress links Geminin depletion to centrosome amplification}},
author = {I. B. Santos and D. M. Glover},
howpublished = {bioRxiv},
year = {2026},
month = jun,
doi = {10.64898/2026.06.30.735730},
url = {https://www.biorxiv.org/content/10.64898/2026.06.30.735730v3},
note = {CC BY},
}
RIS
TY - UNPB
TI - Replication stress links Geminin depletion to centrosome amplification
AU - I. B. Santos
AU - D. M. Glover
PY - 2026
DA - 2026/06/30
PB - bioRxiv
DO - 10.64898/2026.06.30.735730
UR - https://www.biorxiv.org/content/10.64898/2026.06.30.735730v3
AB - The timing of DNA replication and centrosome duplication is tightly regulated with cell cycle progression to ensure the faithful duplication of the genome during cell division. Both DNA and centrosomes are licensed for replication in late telophase/early G1, replicated in S phase and segregated during mitosis; yet how defects in DNA replication licensing are coupled to centrosome homeostasis remains poorly understood. Here, we show that depletion of the replication licensing inhibitor Geminin in proliferating mouse embryonic fibroblasts induces robust centrosome amplification together with impaired primary cilium assembly. Rather than promoting whole-genome reduplication, knockdown of Geminin triggers a replication stress response, characterized by DNA damage accumulation throughout the cycle, and activation of an ATR-dependent DNA damage response. Mechanistically, Geminin depletion-induced replication stress activates the ATR-Chk1-Wee1 checkpoint axis prolonging G2 and leading to premature centriole disengagement and centrosome amplification. These findings identify replication stress as the signaling module that couples defective DNA replication licensing to centrosome amplification.
ER -