A comprehensive model for the proliferation-quiescence decision in response to endogenous DNA damage in human cells

Proceedings of the National Academy of Sciences of the United States of America
Frank S HeldtBéla Novák

Abstract

Human cells that suffer mild DNA damage can enter a reversible state of growth arrest known as quiescence. This decision to temporarily exit the cell cycle is essential to prevent the propagation of mutations, and most cancer cells harbor defects in the underlying control system. Here we present a mechanistic mathematical model to study the proliferation-quiescence decision in nontransformed human cells. We show that two bistable switches, the restriction point (RP) and the G1/S transition, mediate this decision by integrating DNA damage and mitogen signals. In particular, our data suggest that the cyclin-dependent kinase inhibitor p21 (Cip1/Waf1), which is expressed in response to DNA damage, promotes quiescence by blocking positive feedback loops that facilitate G1 progression downstream of serum stimulation. Intriguingly, cells exploit bistability in the RP to convert graded p21 and mitogen signals into an all-or-nothing cell-cycle response. The same mechanism creates a window of opportunity where G1 cells that have passed the RP can revert to quiescence if exposed to DNA damage. We present experimental evidence that cells gradually lose this ability to revert to quiescence as they progress through G1 and that the onset of r...Continue Reading

References

Aug 1, 1985·Proceedings of the National Academy of Sciences of the United States of America·A Zetterberg, O Larsson
Apr 1, 1974·Proceedings of the National Academy of Sciences of the United States of America·A B Pardee
Nov 19, 1993·Cell·W S el-DeiryB Vogelstein
Dec 1, 1995·Current Opinion in Cell Biology·A ZetterbergK G Wiman
Dec 6, 1996·Science·C J Sherr
Mar 10, 2000·Science·T ChengD T Scadden
Mar 21, 2002·Nature Reviews. Cancer·M Malumbres, M Barbacid
Mar 22, 2003·Current Opinion in Cell Biology·John J TysonBela Novak
Jan 28, 2004·Cell·Andrew W Murray
May 6, 2004·Journal of Cell Science·Maxim V Frolov, Nicholas J Dyson
Sep 15, 2004·Trends in Biochemical Sciences·Adrian P BrackenKristian Helin
Oct 2, 2004·Nature Reviews. Molecular Cell Biology·Jiri BartekJiri Lukas
Nov 19, 2004·Nature·Joan Massagué
Dec 3, 2005·Computational Biology and Chemistry·James M McCollumNagiza F Samatova
Oct 14, 2006·Annual Review of Physical Chemistry·Daniel T Gillespie
May 22, 2007·Cell·George-Lucian MoldovanStefan Jentsch
Mar 28, 2008·Nature Cell Biology·Guang YaoLingchong You
Sep 25, 2008·Nature Reviews. Molecular Cell Biology·Helfrid HocheggerTim Hunt
May 15, 2009·Nature Reviews. Cancer·Tarek Abbas, Anindya Dutta
Dec 14, 2011·Trends in Cell Biology·Natalia G Starostina, Edward T Kipreos
Jul 24, 2013·Nature Reviews. Molecular Cell Biology·Cosetta BertoliRobertus A M de Bruin
Jun 7, 2014·Interface Focus·Guang Yao
Oct 1, 2014·Proceedings of the National Academy of Sciences of the United States of America·K Wesley OvertonClifford L Wang
Nov 22, 2014·Nucleic Acids Research·Vijayalakshmi ChelliahCamille Laibe
May 3, 2016·Cell Systems·Alexis R BarrBéla Novák
May 18, 2017·Cell Reports·Mansi AroraSabrina L Spencer
Jun 24, 2017·Bioinformatics·Sam CooperChris Bakal
Nov 6, 2017·Cell Systems·Hui Xiao ChaoJeremy E Purvis

❮ Previous
Next ❯

Citations

Aug 17, 2018·Proceedings of the National Academy of Sciences of the United States of America·Justin MoserSabrina L Spencer
Jun 22, 2020·FEBS Letters·Betheney R Pennycook, Alexis R Barr
Mar 20, 2019·Molecular Systems Biology·Hui Xiao ChaoJeremy E Purvis
Aug 14, 2020·Journal of Clinical Medicine·Zihao Chen, Chunhe Li
Jul 16, 2020·Nature Communications·Betheney R PennycookRobertus A M de Bruin
Oct 1, 2019·FEBS Letters·Wayne StallaertJeremy E Purvis
Nov 10, 2020·Nucleic Acids Research·Samuel HumeKristijan Ramadan
Nov 28, 2020·Human Reproduction·Kashmira BaneGeetanjali Sachdeva
Jan 17, 2021·Biophysical Journal·Harish VenkatachalapathyCasim A Sarkar
Nov 15, 2020·Nature Communications·Nathan C BalukoffStephen Lee
Feb 2, 2021·Science Advances·Jenny F NathansSteven D Cappell
Jan 14, 2020·Current Biology : CB·Frank S HeldtBéla Novák
Apr 11, 2021·Communications Biology·Madeleine HartViji M Draviam
Sep 19, 2020·Molecular Cell·Seth M RubinJan M Skotheim
Mar 24, 2021·The FEBS Journal·Kyoichi EbataMariko Okada
Jul 27, 2021·Frontiers in Cell and Developmental Biology·Anna Julia WiecekMaria Secrier
Aug 10, 2021·Frontiers in Cell and Developmental Biology·Robert F Brooks

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.