TY - JOUR

T1 - A unified model for the G1/S cell cycle transition

AU - Hume, Samuel

AU - Dianov, Grigory L.

AU - Ramadan, Kristijan

N1 - Publisher Copyright: © The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2020/12/16

Y1 - 2020/12/16

N2 - Efficient S phase entry is essential for development, tissue repair, and immune defences. However, hyperactive or expedited S phase entry causes replication stress, DNA damage and oncogenesis, highlighting the need for strict regulation. Recent paradigm shifts and conflicting reports demonstrate the requirement for a discussion of the G1/S transition literature. Here, we review the recent studies, and propose a unified model for the S phase entry decision. In this model, competition between mitogen and DNA damage signalling over the course of the mother cell cycle constitutes the predominant control mechanism for S phase entry of daughter cells. Mitogens and DNA damage have distinct sensing periods, giving rise to three Commitment Points for S phase entry (CP1-3). S phase entry is mitogen-independent in the daughter G1 phase, but remains sensitive to DNA damage, such as single strand breaks, the most frequently-occurring lesions that uniquely threaten DNA replication. To control CP1-3, dedicated hubs integrate the antagonistic mitogenic and DNA damage signals, regulating the stoichiometric cyclin: CDK inhibitor ratio for ultrasensitive control of CDK4/6 and CDK2. This unified model for the G1/S cell cycle transition combines the findings of decades of study, and provides an updated foundation for cell cycle research.

AB - Efficient S phase entry is essential for development, tissue repair, and immune defences. However, hyperactive or expedited S phase entry causes replication stress, DNA damage and oncogenesis, highlighting the need for strict regulation. Recent paradigm shifts and conflicting reports demonstrate the requirement for a discussion of the G1/S transition literature. Here, we review the recent studies, and propose a unified model for the S phase entry decision. In this model, competition between mitogen and DNA damage signalling over the course of the mother cell cycle constitutes the predominant control mechanism for S phase entry of daughter cells. Mitogens and DNA damage have distinct sensing periods, giving rise to three Commitment Points for S phase entry (CP1-3). S phase entry is mitogen-independent in the daughter G1 phase, but remains sensitive to DNA damage, such as single strand breaks, the most frequently-occurring lesions that uniquely threaten DNA replication. To control CP1-3, dedicated hubs integrate the antagonistic mitogenic and DNA damage signals, regulating the stoichiometric cyclin: CDK inhibitor ratio for ultrasensitive control of CDK4/6 and CDK2. This unified model for the G1/S cell cycle transition combines the findings of decades of study, and provides an updated foundation for cell cycle research.

KW - Cell Cycle/genetics

KW - Cell Cycle Checkpoints/genetics

KW - Cell Division/genetics

KW - DNA Damage/genetics

KW - DNA Replication/genetics

KW - G1 Phase/genetics

KW - Humans

KW - S Phase/genetics

KW - Signal Transduction/genetics

UR - http://www.scopus.com/inward/record.url?scp=85098531866&partnerID=8YFLogxK

U2 - 10.1093/nar/gkaa1002

DO - 10.1093/nar/gkaa1002

M3 - Review article

C2 - 33166394

AN - SCOPUS:85098531866

VL - 48

SP - 12483

EP - 12501

JO - Nucleic Acids Research

JF - Nucleic Acids Research

SN - 0305-1048

IS - 22

ER -