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Article ; Online: CDT1 inhibits CMG helicase in early S phase to separate origin licensing from DNA synthesis

Ratnayeke, Nalin / Baris, Yasemin / Chung, Mingyu / Yeeles, Joseph T.P. / Meyer, Tobias

Molecular Cell. 2023 Jan., v. 83, no. 1 p.26-42.e13

2023

Abstract: Human cells license tens of thousands of origins of replication in G1 and then must stop all licensing before DNA synthesis in S phase to prevent re-replication and genome instability that ensue when an origin is licensed on replicated DNA. However, the ... ...

Abstract	Human cells license tens of thousands of origins of replication in G1 and then must stop all licensing before DNA synthesis in S phase to prevent re-replication and genome instability that ensue when an origin is licensed on replicated DNA. However, the E3 ubiquitin ligase CRL4Cᵈᵗ² only starts to degrade the licensing factor CDT1 after origin firing, raising the question of how cells prevent re-replication before CDT1 is fully degraded. Here, using quantitative microscopy and in-vitro-reconstituted human DNA replication, we show that CDT1 inhibits DNA synthesis during an overlap period when CDT1 is still present after origin firing. CDT1 inhibits DNA synthesis by suppressing CMG helicase at replication forks, and DNA synthesis commences once CDT1 is degraded. Thus, in contrast to the prevailing model that human cells prevent re-replication by strictly separating licensing from firing, licensing and firing overlap, and cells instead separate licensing from DNA synthesis.
Keywords	DNA ; DNA replication ; genetic instability ; humans ; interphase ; microscopy ; models ; ubiquitin-protein ligase ; re-replication ; genome integrity ; licensing factor ; CDT1 ; CMG helicase ; replication fork
Language	English
Dates of publication	2023-01
Size	p. 26-42.e13.
Publishing place	Elsevier Inc.
Document type	Article ; Online
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2022.12.004
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: A fast-acting lipid checkpoint in G1 prevents mitotic defects.

Köberlin, Marielle S / Fan, Yilin / Liu, Chad / Chung, Mingyu / Pinto, Antonio F M / Jackson, Peter K / Saghatelian, Alan / Meyer, Tobias

Nature communications

2024 Volume 15, Issue 1, Page(s) 2441

Abstract: Lipid synthesis increases during the cell cycle to ensure sufficient membrane mass, but how insufficient synthesis restricts cell-cycle entry is not understood. Here, we identify a lipid checkpoint in G1 phase of the mammalian cell cycle by using live ... ...

Abstract	Lipid synthesis increases during the cell cycle to ensure sufficient membrane mass, but how insufficient synthesis restricts cell-cycle entry is not understood. Here, we identify a lipid checkpoint in G1 phase of the mammalian cell cycle by using live single-cell imaging, lipidome, and transcriptome analysis of a non-transformed cell. We show that synthesis of fatty acids in G1 not only increases lipid mass but extensively shifts the lipid composition to unsaturated phospholipids and neutral lipids. Strikingly, acute lowering of lipid synthesis rapidly activates the PERK/ATF4 endoplasmic reticulum (ER) stress pathway that blocks cell-cycle entry by increasing p21 levels, decreasing Cyclin D levels, and suppressing Retinoblastoma protein phosphorylation. Together, our study identifies a rapid anticipatory ER lipid checkpoint in G1 that prevents cells from starting the cell cycle as long as lipid synthesis is low, thereby preventing mitotic defects, which are triggered by low lipid synthesis much later in mitosis.
MeSH term(s)	Animals ; Cell Cycle ; G1 Phase ; Mitosis ; Phosphorylation ; Lipids ; Mammals
Chemical Substances	Lipids
Language	English
Publishing date	2024-03-18
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-46696-9
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Article ; Online: Clinical CDK4/6 inhibitors induce selective and immediate dissociation of p21 from cyclin D-CDK4 to inhibit CDK2.

Pack, Lindsey R / Daigh, Leighton H / Chung, Mingyu / Meyer, Tobias

Nature communications

2021 Volume 12, Issue 1, Page(s) 3356

Abstract: Since their discovery as drivers of proliferation, cyclin-dependent kinases (CDKs) have been considered therapeutic targets. Small molecule inhibitors of CDK4/6 are used and tested in clinical trials to treat multiple cancer types. Despite their clinical ...

Abstract	Since their discovery as drivers of proliferation, cyclin-dependent kinases (CDKs) have been considered therapeutic targets. Small molecule inhibitors of CDK4/6 are used and tested in clinical trials to treat multiple cancer types. Despite their clinical importance, little is known about how CDK4/6 inhibitors affect the stability of CDK4/6 complexes, which bind cyclins and inhibitory proteins such as p21. We develop an assay to monitor CDK complex stability inside the nucleus. Unexpectedly, treatment with CDK4/6 inhibitors-palbociclib, ribociclib, or abemaciclib-immediately dissociates p21 selectively from CDK4 but not CDK6 complexes. This effect mediates indirect inhibition of CDK2 activity by p21 but not p27 redistribution. Our work shows that CDK4/6 inhibitors have two roles: non-catalytic inhibition of CDK2 via p21 displacement from CDK4 complexes, and catalytic inhibition of CDK4/6 independent of p21. By broadening the non-catalytic displacement to p27 and CDK6 containing complexes, next-generation CDK4/6 inhibitors may have improved efficacy and overcome resistance mechanisms.
MeSH term(s)	Animals ; Cell Cycle/drug effects ; Cell Line ; Cell Nucleus/drug effects ; Cell Nucleus/metabolism ; Cyclin D/metabolism ; Cyclin-Dependent Kinase 2/antagonists & inhibitors ; Cyclin-Dependent Kinase 2/genetics ; Cyclin-Dependent Kinase 2/metabolism ; Cyclin-Dependent Kinase 4/antagonists & inhibitors ; Cyclin-Dependent Kinase 4/genetics ; Cyclin-Dependent Kinase 4/metabolism ; Cyclin-Dependent Kinase 6/antagonists & inhibitors ; Cyclin-Dependent Kinase 6/genetics ; Cyclin-Dependent Kinase 6/metabolism ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Cyclin-Dependent Kinase Inhibitor p27/metabolism ; Epithelial Cells/drug effects ; Epithelial Cells/metabolism ; Humans ; MCF-7 Cells ; Mice ; Microscopy, Fluorescence ; Piperazines/pharmacology ; Protein Binding ; Protein Kinase Inhibitors/pharmacology ; Pyridines/pharmacology ; Retinal Pigment Epithelium/cytology ; Retinal Pigment Epithelium/drug effects ; Retinal Pigment Epithelium/metabolism
Chemical Substances	Cyclin D ; Cyclin-Dependent Kinase Inhibitor p21 ; Piperazines ; Protein Kinase Inhibitors ; Pyridines ; Cyclin-Dependent Kinase Inhibitor p27 (147604-94-2) ; CDK2 protein, human (EC 2.7.11.22) ; CDK4 protein, human (EC 2.7.11.22) ; CDK6 protein, human (EC 2.7.11.22) ; Cyclin-Dependent Kinase 2 (EC 2.7.11.22) ; Cyclin-Dependent Kinase 4 (EC 2.7.11.22) ; Cyclin-Dependent Kinase 6 (EC 2.7.11.22) ; palbociclib (G9ZF61LE7G)
Language	English
Publishing date	2021-06-07
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-021-23612-z
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Article ; Online: CDT1 inhibits CMG helicase in early S phase to separate origin licensing from DNA synthesis.

Ratnayeke, Nalin / Baris, Yasemin / Chung, Mingyu / Yeeles, Joseph T P / Meyer, Tobias

Molecular cell

2022 Volume 83, Issue 1, Page(s) 26–42.e13

Abstract	Human cells license tens of thousands of origins of replication in G1 and then must stop all licensing before DNA synthesis in S phase to prevent re-replication and genome instability that ensue when an origin is licensed on replicated DNA. However, the E3 ubiquitin ligase CRL4
MeSH term(s)	Humans ; S Phase ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; DNA Replication ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism ; DNA/genetics ; DNA Helicases/genetics ; DNA Helicases/metabolism
Chemical Substances	Cell Cycle Proteins ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; DNA (9007-49-2) ; DNA Helicases (EC 3.6.4.-) ; CDT1 protein, human
Language	English
Publishing date	2022-12-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2022.12.004
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Book ; Online: Rethinking Backdoor Attacks on Dataset Distillation

Chung, Ming-Yu / Chou, Sheng-Yen / Yu, Chia-Mu / Chen, Pin-Yu / Kuo, Sy-Yen / Ho, Tsung-Yi

A Kernel Method Perspective

2023

Abstract: Dataset distillation offers a potential means to enhance data efficiency in deep learning. Recent studies have shown its ability to counteract backdoor risks present in original training samples. In this study, we delve into the theoretical aspects of ... ...

Abstract	Dataset distillation offers a potential means to enhance data efficiency in deep learning. Recent studies have shown its ability to counteract backdoor risks present in original training samples. In this study, we delve into the theoretical aspects of backdoor attacks and dataset distillation based on kernel methods. We introduce two new theory-driven trigger pattern generation methods specialized for dataset distillation. Following a comprehensive set of analyses and experiments, we show that our optimization-based trigger design framework informs effective backdoor attacks on dataset distillation. Notably, datasets poisoned by our designed trigger prove resilient against conventional backdoor attack detection and mitigation methods. Our empirical results validate that the triggers developed using our approaches are proficient at executing resilient backdoor attacks. Comment: 19 pages, 4 figures
Keywords	Computer Science - Machine Learning ; Computer Science - Cryptography and Security
Subject code	006
Publishing date	2023-11-28
Publishing country	us
Document type	Book ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Transient Hysteresis in CDK4/6 Activity Underlies Passage of the Restriction Point in G1.

Chung, Mingyu / Liu, Chad / Yang, Hee Won / Köberlin, Marielle S / Cappell, Steven D / Meyer, Tobias

Molecular cell

2019 Volume 76, Issue 4, Page(s) 562–573.e4

Abstract: Cells escape the need for mitogens at a restriction point several hours before entering S phase. The restriction point has been proposed to result from CDK4/6 initiating partial Rb phosphorylation to trigger a bistable switch whereby cyclin E-CDK2 and Rb ...

Abstract	Cells escape the need for mitogens at a restriction point several hours before entering S phase. The restriction point has been proposed to result from CDK4/6 initiating partial Rb phosphorylation to trigger a bistable switch whereby cyclin E-CDK2 and Rb mutually reinforce each other to induce Rb hyperphosphorylation. Here, using single-cell analysis, we unexpectedly found that cyclin E/A-CDK activity can only maintain Rb hyperphosphorylation starting at the onset of S phase and that CDK4/6 activity, but not cyclin E/A-CDK activity, is required to hyperphosphorylate Rb throughout G1 phase. Mitogen removal in G1 results in a gradual loss of CDK4/6 activity with a high likelihood of cells sustaining Rb hyperphosphorylation until S phase, at which point cyclin E/A-CDK activity takes over. Thus, it is short-term memory, or transient hysteresis, in CDK4/6 activity following mitogen removal that sustains Rb hyperphosphorylation, demonstrating a probabilistic rather than an irreversible molecular mechanism underlying the restriction point.
MeSH term(s)	Animals ; Cell Line ; Cell Proliferation ; Cyclin-Dependent Kinase 4/metabolism ; Cyclin-Dependent Kinase 6/metabolism ; Dose-Response Relationship, Drug ; Epithelial Cells/drug effects ; Epithelial Cells/enzymology ; Fibroblasts/drug effects ; Fibroblasts/enzymology ; G1 Phase Cell Cycle Checkpoints ; Human Umbilical Vein Endothelial Cells/drug effects ; Human Umbilical Vein Endothelial Cells/enzymology ; Humans ; Mice ; Mitogens/pharmacology ; Models, Biological ; Phosphorylation ; Retinoblastoma Binding Proteins/metabolism ; Signal Transduction ; Time Factors ; Ubiquitin-Protein Ligases/metabolism
Chemical Substances	Mitogens ; RB1 protein, human ; Retinoblastoma Binding Proteins ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; CDK4 protein, human (EC 2.7.11.22) ; CDK6 protein, human (EC 2.7.11.22) ; Cyclin-Dependent Kinase 4 (EC 2.7.11.22) ; Cyclin-Dependent Kinase 6 (EC 2.7.11.22)
Language	English
Publishing date	2019-09-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2019.08.020
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Article ; Online: Competing memories of mitogen and p53 signalling control cell-cycle entry.

Yang, Hee Won / Chung, Mingyu / Kudo, Takamasa / Meyer, Tobias

Nature

2017 Volume 549, Issue 7672, Page(s) 404–408

Abstract: Regulation of cell proliferation is necessary for immune responses, tissue repair, and upkeep of organ function to maintain human health. When proliferating cells complete mitosis, a fraction of newly born daughter cells immediately enter the next cell ... ...

Abstract	Regulation of cell proliferation is necessary for immune responses, tissue repair, and upkeep of organ function to maintain human health. When proliferating cells complete mitosis, a fraction of newly born daughter cells immediately enter the next cell cycle, while the remaining cells in the same population exit to a transient or persistent quiescent state. Whether this choice between two cell-cycle pathways is due to natural variability in mitogen signalling or other underlying causes is unknown. Here we show that human cells make this fundamental cell-cycle entry or exit decision based on competing memories of variable mitogen and stress signals. Rather than erasing their signalling history at cell-cycle checkpoints before mitosis, mother cells transmit DNA damage-induced p53 protein and mitogen-induced cyclin D1 (CCND1) mRNA to newly born daughter cells. After mitosis, the transferred CCND1 mRNA and p53 protein induce variable expression of cyclin D1 and the CDK inhibitor p21 that almost exclusively determines cell-cycle commitment in daughter cells. We find that stoichiometric inhibition of cyclin D1-CDK4 activity by p21 controls the retinoblastoma (Rb) and E2F transcription program in an ultrasensitive manner. Thus, daughter cells control the proliferation-quiescence decision by converting the memories of variable mitogen and stress signals into a competition between cyclin D1 and p21 expression. We propose a cell-cycle control principle based on natural variation, memory and competition that maximizes the health of growing cell populations.
MeSH term(s)	Cell Cycle/physiology ; Cell Cycle Checkpoints ; Cell Proliferation ; Cyclin D1/antagonists & inhibitors ; Cyclin D1/genetics ; Cyclin-Dependent Kinase 4/antagonists & inhibitors ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; DNA Damage ; E2F Transcription Factors/metabolism ; Humans ; Mitogens/metabolism ; Mitosis ; Retinoblastoma/metabolism ; Retinoblastoma/pathology ; Signal Transduction ; Stress, Physiological ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	CCND1 protein, human ; Cyclin-Dependent Kinase Inhibitor p21 ; E2F Transcription Factors ; Mitogens ; TP53 protein, human ; Tumor Suppressor Protein p53 ; Cyclin D1 (136601-57-5) ; CDK4 protein, human (EC 2.7.11.22) ; Cyclin-Dependent Kinase 4 (EC 2.7.11.22)
Language	English
Publishing date	2017-09-06
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/nature23880
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Article ; Online: Multiomics reveals glutathione metabolism as a driver of bimodality during stem cell aging.

Benjamin, Daniel I / Brett, Jamie O / Both, Pieter / Benjamin, Joel S / Ishak, Heather L / Kang, Jengmin / Kim, Soochi / Chung, Mingyu / Arjona, Marina / Nutter, Christopher W / Tan, Jenna H / Krishnan, Ananya K / Dulay, Hunter / Louie, Sharon M / de Morree, Antoine / Nomura, Daniel K / Rando, Thomas A

Cell metabolism

2023 Volume 35, Issue 3, Page(s) 472–486.e6

Abstract: With age, skeletal muscle stem cells (MuSCs) activate out of quiescence more slowly and with increased death, leading to defective muscle repair. To explore the molecular underpinnings of these defects, we combined multiomics, single-cell measurements, ... ...

Abstract	With age, skeletal muscle stem cells (MuSCs) activate out of quiescence more slowly and with increased death, leading to defective muscle repair. To explore the molecular underpinnings of these defects, we combined multiomics, single-cell measurements, and functional testing of MuSCs from young and old mice. The multiomics approach allowed us to assess which changes are causal, which are compensatory, and which are simply correlative. We identified glutathione (GSH) metabolism as perturbed in old MuSCs, with both causal and compensatory components. Contrary to young MuSCs, old MuSCs exhibit a population dichotomy composed of GSH
MeSH term(s)	Mice ; Animals ; Muscle, Skeletal/metabolism ; Multiomics ; Stem Cells/metabolism ; Cellular Senescence ; Aging/physiology
Language	English
Publishing date	2023-02-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2176834-1
ISSN	1932-7420 ; 1550-4131
ISSN (online)	1932-7420
ISSN	1550-4131
DOI	10.1016/j.cmet.2023.02.001
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Article ; Online: Altered G1 signaling order and commitment point in cells proliferating without CDK4/6 activity.

Liu, Chad / Konagaya, Yumi / Chung, Mingyu / Daigh, Leighton H / Fan, Yilin / Yang, Hee Won / Terai, Kenta / Matsuda, Michiyuki / Meyer, Tobias

Nature communications

2020 Volume 11, Issue 1, Page(s) 5305

Abstract: Cell-cycle entry relies on an orderly progression of signaling events. To start, cells first activate the kinase cyclin D-CDK4/6, which leads to eventual inactivation of the retinoblastoma protein Rb. Hours later, cells inactivate APC/ ... ...

Abstract	Cell-cycle entry relies on an orderly progression of signaling events. To start, cells first activate the kinase cyclin D-CDK4/6, which leads to eventual inactivation of the retinoblastoma protein Rb. Hours later, cells inactivate APC/C
MeSH term(s)	Animals ; Cell Line ; Cell Proliferation ; Cyclin-Dependent Kinase 4/genetics ; Cyclin-Dependent Kinase 4/metabolism ; Cyclin-Dependent Kinase 6/genetics ; Cyclin-Dependent Kinase 6/metabolism ; Female ; G1 Phase ; Humans ; Male ; Mice ; Retinoblastoma Protein/genetics ; Retinoblastoma Protein/metabolism ; Signal Transduction
Chemical Substances	Retinoblastoma Protein ; Cyclin-Dependent Kinase 4 (EC 2.7.11.22) ; Cyclin-Dependent Kinase 6 (EC 2.7.11.22)
Language	English
Publishing date	2020-10-20
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-020-18966-9
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Article: Stochastic Endogenous Replication Stress Causes ATR-Triggered Fluctuations in CDK2 Activity that Dynamically Adjust Global DNA Synthesis Rates.

Daigh, Leighton H / Liu, Chad / Chung, Mingyu / Cimprich, Karlene A / Meyer, Tobias

Cell systems

2018 Volume 7, Issue 1, Page(s) 17–27.e3

Abstract: Faithful DNA replication is challenged by stalling of replication forks during S phase. Replication stress is further increased in cancer cells or in response to genotoxic insults. Using live single-cell image analysis, we found that CDK2 activity ... ...

Abstract	Faithful DNA replication is challenged by stalling of replication forks during S phase. Replication stress is further increased in cancer cells or in response to genotoxic insults. Using live single-cell image analysis, we found that CDK2 activity fluctuates throughout an unperturbed S phase. We show that CDK2 fluctuations result from transient ATR signals triggered by stochastic replication stress events. In turn, fluctuating endogenous CDK2 activity causes corresponding decreases and increases in DNA synthesis rates, linking changes in stochastic replication stress to fluctuating global DNA replication rates throughout S phase. Moreover, cells that re-enter the cell cycle after mitogen stimulation have increased CDK2 fluctuations and prolonged S phase resulting from increased replication stress-induced CDK2 suppression. Thus, our study reveals a dynamic control principle for DNA replication whereby CDK2 activity is suppressed and fluctuates throughout S phase to continually adjust global DNA synthesis rates in response to recurring stochastic replication stress events.
MeSH term(s)	Ataxia Telangiectasia Mutated Proteins/genetics ; Ataxia Telangiectasia Mutated Proteins/metabolism ; Cell Cycle/physiology ; Cell Cycle Proteins/genetics ; Cell Division ; Cell Line ; Cyclin-Dependent Kinase 2/metabolism ; Cyclin-Dependent Kinase 2/physiology ; Cyclin-Dependent Kinases/genetics ; DNA/biosynthesis ; DNA Damage ; DNA Replication ; DNA-Binding Proteins/genetics ; Humans ; MCF-7 Cells ; S Phase/physiology ; Single-Cell Analysis/methods
Chemical Substances	Cell Cycle Proteins ; DNA-Binding Proteins ; DNA (9007-49-2) ; ATR protein, human (EC 2.7.11.1) ; Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1) ; CDK2 protein, human (EC 2.7.11.22) ; Cyclin-Dependent Kinase 2 (EC 2.7.11.22) ; Cyclin-Dependent Kinases (EC 2.7.11.22)
Language	English
Publishing date	2018-06-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2854138-8
ISSN	2405-4720 ; 2405-4712
ISSN (online)	2405-4720
ISSN	2405-4712
DOI	10.1016/j.cels.2018.05.011
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