Dosage of Dyrk1a shifts cells within a p21-cyclin D1 signaling map to control the decision to enter the cell cycle
Open accessAbstract
Summary Mammalian cells have a remarkable capacity to compensate for heterozygous gene loss or extra gene copies. One exception is Down syndrome (DS) where a third copy of chromosome 21 mediates neurogenesis defects and lowers the frequency of solid tumors. Here we combine live-cell imaging and single-cell analysis to show that increased dosage of chromosome 21-localized Dyrk1a steeply increases G1 cell cycle duration through direct phosphorylation and degradation of cyclin D1 (CycD1). DS-derived fibroblasts showed analogous cell cycle changes that were reversed by Dyrk1a inhibition. Furthermore, reducing Dyrk1a activity increased CycD1 expression to force a bifurcation, with one subpopulation of cells accelerating proliferation and the other arresting proliferation by co-stabilizing CycD1 and the CDK inhibitor p21. Thus, dosage of Dyrk1a repositions cells within a p21-CycD1 signaling map, directing each cell to either proliferate or to follow two distinct cell cycle exit pathways characterized by high or low CycD1 and p21 levels.
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Dyrk1A phosphorylates cyclin D1 on T286, stimulating cytoplasmic relocalization and proteasomal degradation, which is required for proper regulation of the G1-S phase transition and control of cellular proliferation.
“Among these, we further characterized Dyrk1A, a dual specificity kinase that phosphorylates the proto-oncoprotein cyclin D1 on threonine 286 (T286), thereby stimulating its timely cytoplasmic relocalization and proteasomal degradation, which is required for proper regulation of the G1-S phase transition and control of cellular proliferation.”
From A genome-wide screen reveals that Dyrk1A kinase promotes nucleotide excision repair by preventing aberrant overexpression of cyclin D1 and p21 (2023) · cites this paper as [16]
The Results section (“Dyrk1a degrades CycD1 by direct phosphorylation of CycD1 at Thr286”; page unavailable) reports direct T286 phosphorylation, proteasome-driven cyclin D1 degradation, and effects on the fraction of cycling cells. The passages do not establish the claimed cytoplasmic relocalization, so that mechanistic step is unsupported by our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredFlag-HA-cyclin D1 (T286A) was expressed at higher levels than either Flag-HA-WT cyclin D1 or endogenous WT cyclin D1 in WM1366 cells.
“As expected, Flag-HA-cyclin D1 (T286A) (hereafter cyclin D1 [T286A]) was expressed at higher levels than either Flag-HA-WT cyclin D1 or endogenous WT cyclin D1 (Fig. 4D) (16).”
From A genome-wide screen reveals that Dyrk1A kinase promotes nucleotide excision repair by preventing aberrant overexpression of cyclin D1 and p21 (2023) · cites this paper as [16]
The Results section, “Dyrk1a degrades CycD1 by direct phosphorylation of CycD1 at Thr286” (page unavailable), reports that HA-tagged cyclin D1 T286A remained at a high level upon Dyrk1a induction, unlike HA-tagged WT cyclin D1. It does not establish the claimed expression comparison in WM1366 cells or compare T286A with endogenous WT cyclin D1. (LLM, conf=0.86)
Experimental — accuracy not yet measuredDyrk1A regulates S phase NER through phosphorylation of cyclin D1 on T286.
“Rather we found that Dyrk1A regulates S phase NER through phosphorylation of cyclin D1 on T286 (16), a modification that promotes cyclin D1 nuclear export and proteolytic degradation (40, 41).”
From A genome-wide screen reveals that Dyrk1A kinase promotes nucleotide excision repair by preventing aberrant overexpression of cyclin D1 and p21 (2023) · cites this paper as [16]
The Results section, “Dyrk1a degrades CycD1 by direct phosphorylation of CycD1 at Thr286” (page unavailable), reports that Dyrk1a phosphorylates cyclin D1 at T286 and thereby regulates its degradation and cell-cycle entry. The paper discusses the fraction of cells entering S phase, but the passages do not address nucleotide excision repair (NER) or show that this phosphorylation regulates S-phase NER. (LLM, conf=0.89)
Experimental — accuracy not yet measuredDyrk1A-dependent phosphorylation of cyclin D1 prevents premature entry into S phase and concomitant genomic instability/enhanced cellular proliferation.
“As such, Dyrk1A-dependent phosphorylation of cyclin D1 prevents premature entry into S phase and concomitant genomic instability/enhanced cellular proliferation (16).”
From A genome-wide screen reveals that Dyrk1A kinase promotes nucleotide excision repair by preventing aberrant overexpression of cyclin D1 and p21 (2023) · cites this paper as [16]
The Results section on cyclin D1 Thr286 phosphorylation reports that Dyrk1A promotes cyclin D1 degradation and regulates the fraction of cycling cells. The Results section on G1 duration also reports that Dyrk1A inhibition shortens G1, while the section on cyclin D1 expression links inhibition to increased proliferation. The paper does not establish that this mechanism prevents genomic instability. (LLM, conf=0.88)
Experimental — accuracy not yet measuredDyrk1A depletion increases p21 levels in a cyclin D1-dependent manner.
“Dyrk1A depletion was previously shown to increase the levels of p21 in a cyclin D1–dependent manner (16).”
From A genome-wide screen reveals that Dyrk1A kinase promotes nucleotide excision repair by preventing aberrant overexpression of cyclin D1 and p21 (2023) · cites this paper as [16]
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References 35 · Cited by 144
- Authors
- Chen, J.-Y., Lin, J.-R., Tsai, F.-C., & Meyer, T.
- Affiliations
- Stanford University (US)
- Corresponding author
- Meyer, Tobias
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2013-10
- Volume
- 52
- Issue
- 1
- Pages
- 87-100
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC4039290
- OpenAlex
- W2012258557
- Semantic Scholar
- 5d6c67eb044b92a2ad4194ddee436e41c3b1a658
- Cited by
- 144
- References
- 35
- Citations by year
- 2026: 17 · 2025: 5 · 2024: 15 · 2023: 16 · 2022: 12 · 2021: 17 · 2020: 12 · 2019: 4 · 2018: 8 · 2017: 17 · 2016: 8 · 2015: 10 · 2014: 3
- FWCI
- 3.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R01MH064801, MH64801)
- National Institute of General Medical Sciences (R01GM030179)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- DYRK1A, cyclin D1, p21, Down syndrome, cell cycle entry, G1 phase duration, protein phosphorylation, protein degradation, cell cycle exit, cell proliferation, dosage compensation, single-cell analysis, live-cell imaging
- MeSH terms
- Dyrk Kinases, Chromosomes, Human, Pair 21, Down Syndrome, Fibroblasts, Gene Expression Regulation, Humans, Microscopy, Fluorescence, Phosphorylation, Protein-Tyrosine Kinases, Time Factors, Transfection, Signal Transduction, G1 Phase, Protein Serine-Threonine Kinases, ras Proteins, Microscopy, Video, Cyclin D1, RNA Interference, Cell Line, Tumor, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p21, Protein Stability, Gene Knockdown Techniques, Cell Tracking, Time-Lapse Imaging
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