Intrinsic checkpoint deficiency during cell cycle re-entry from quiescence

• Type of Material: Article
• Authors: Jacob P Matson, The University of North Carolina at Chapel Hill; Amy M House, The University of North Carolina at Chapel Hill; Gavin D Grant, The University of North Carolina at Chapel Hill; Huaitong Wu, The University of North Carolina at Chapel Hill; Joanna Perez, Emory University; Jeanette Gowen Cook, The University of North Carolina at Chapel Hill
• Language: English
• Date: 2019-01-01
• Publisher: Rockefeller University Press
• Publication Version: Final Published Version
• Copyright Statement: © 2019 Matson et al.
• License: Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1083/jcb.201902143
• Title of Journal or Parent Work: Journal of Cell Biology
• Volume: 218
• Issue: 7
• Start Page: 2169
• End Page: 2184
• Grant/Funding Information: This work was supported by a fellowship from the National Science Foundation (DGE-1144081) to J.P. Matson, a University of North Carolina Dissertation Completion Fellowship to J.P. Matson, and grants from the National Institutes of Health/National Institute of General Medical Sciences to J.G. Cook (GM083024, GM102413, and R25GM089569; R25GM089569 also supported J. Perez). The University of North Carolina Flow Cytometry Core Facility is supported in part by P30 CA016086.
• Keywords: Adaptor Proteins, Signal Transducing; Cell Division; Cell Nucleus; Cell Cycle; Genomic Instability; S Phase; DNA Replication; Replication Origin; Cell Proliferation; Humans; Flow Cytometry; G1 Phase; Nuclear Proteins; Cell Cycle Proteins; Chromatin
• Research Categories: Health Sciences, Oncology; Biology, Cell

Abstract

To maintain tissue homeostasis, cells transition between cell cycle quiescence and proliferation. An essential G1 process is minichromosome maintenance complex (MCM) loading at DNA replication origins to prepare for S phase, known as origin licensing. A p53-dependent origin licensing checkpoint normally ensures sufficient MCM loading before S phase entry. We used quantitative flow cytometry and live cell imaging to compare MCM loading during the long first G1 upon cell cycle entry and the shorter G1 phases in the second and subsequent cycles. We discovered that despite the longer G1 phase, the first G1 after cell cycle re-entry is significantly underlicensed. Consequently, the first S phase cells are hypersensitive to replication stress. This underlicensing results from a combination of slow MCM loading with a severely compromised origin licensing checkpoint. The hypersensitivity to replication stress increases over repeated rounds of quiescence. Thus, underlicensing after cell cycle re-entry from quiescence distinguishes a higher-risk first cell cycle that likely promotes genome instability.