ArticleNucleic acids research2022
Convergence of SIRT1 and ATR signaling to modulate replication origin dormancy.
Article in Nucleic acids research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 28 citations in OpenAlex.
- Polycomb-mediated 3D-genome organization controls replication timing.Science advances · 2026Article
- Replication origin flexibility: a tool to mitigate the hazards of excess replication.Trends in genetics : TIG · 2026Review
- Dynamic regulation of origin firing factors links CDK activity to dormant origin activation.Nature communications · 2026Article
- ATR and TopBP1 oppose to control dormant origin activity and global replication dynamics, providing a first defense against replication stress.Nucleic acids research · 2026Article
- Impact of Tau overexpression on DNA replication dynamics in centromeres of human neural progenitor cells.iScience · 2026Article
- Nuclear DAB2IP regulates DNA replication initiation through activating PLK1-mediated HBO1 phosphorylation.Nucleic acids research · 2025Article
- Selective interactions at pre-replication complexes categorize baseline and dormant origins.Nature communications · 2025Article
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- DNA replication and replication stress response in the context of nuclear architecture.Chromosoma · 2024Review
- SIRT1 Prevents R-Loops during Chronological Aging by Modulating DNA Replication at rDNA Loci.Cells · 2023Article
- Resistance to 2-Hydroxy-Flutamide in Prostate Cancer Cells Is Associated with the Downregulation of Phosphatidylcholine Biosynthesis and Epigenetic Modifications.International journal of molecular sciences · 2023Article
- Neural network and kinetic modelling of human genome replication reveal replication origin locations and strengths.PLoS computational biology · 2023Article
- ORChestra coordinates the replication and repair music.BioEssays : news and reviews in molecular, cellular and developmental biology · 2023Article
- Review
- Claspin-Dependent and -Independent Chk1 Activation by a Panel of Biological Stresses.Biomolecules · 2023Article
- 3D chromatin connectivity underlies replication origin efficiency in mouse embryonic stem cells.Nucleic acids research · 2022Article
- Global landscape of replicative DNA polymerase usage in the human genome.Nature communications · 2022Article
- Exploring the Multi-Faceted Role of Sirtuins in Glioblastoma Pathogenesis and Targeting Options.International journal of molecular sciences · 2022Review
Corrections and comments
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Authors and funding
13 authors at 2 institutions in 1 country.
Funding
Abstract
During routine genome duplication, many potential replication origins remain inactive or 'dormant'. Such origin dormancy is achieved, in part, by an interaction with the metabolic sensor SIRT1 deacetylase. We report here that dormant origins are a group of consistent, pre-determined genomic sequences that are distinguished from baseline (i.e. ordinarily active) origins by their preferential association with two phospho-isoforms of the helicase component MCM2. During normal unperturbed cell growth, baseline origins, but not dormant origins, associate with a form of MCM2 that is phosphorylated by DBF4-dependent kinase (DDK) on serine 139 (pS139-MCM2). This association facilitates the initiation of DNA replication from baseline origins. Concomitantly, SIRT1 inhibits Ataxia Telangiectasia and Rad3-related (ATR)-kinase-mediated phosphorylation of MCM2 on serine 108 (pS108-MCM2) by deacetylating the ATR-interacting protein DNA topoisomerase II binding protein 1 (TOPBP1), thereby preventing ATR recruitment to chromatin. In cells devoid of SIRT1 activity, or challenged by replication stress, this inhibition is circumvented, enabling ATR-mediated S108-MCM2 phosphorylation. In turn, pS108-MCM2 enables DDK-mediated phosphorylation on S139-MCM2 and facilitates replication initiation at dormant origins. These observations suggest that replication origin dormancy and activation are regulated by distinct post-translational MCM modifications that reflect a balance between SIRT1 activity and ATR signaling.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.