A Cyclin A—Myb-MuvB—Aurora B network regulates the choice between mitotic cycles and polyploid endoreplication cycles

Michael D. Rotelli, Robert A. Policastro, Anna M. Bolling, Andrew W. Killion, Abraham J. Weinberg, Michael J. Dixon, Gabriel E. Zentner, Claire Walczak, Mary A. Lilly, Brian R. Calvi

Research output: Contribution to journalArticle

Abstract

Endoreplication is a cell cycle variant that entails cell growth and periodic genome duplication without cell division, and results in large, polyploid cells. Cells switch from mitotic cycles to endoreplication cycles during development, and also in response to conditional stimuli during wound healing, regeneration, aging, and cancer. In this study, we use integrated approaches in Drosophila to determine how mitotic cycles are remodeled into endoreplication cycles, and how similar this remodeling is between induced and developmental endoreplicating cells (iECs and devECs). Our evidence suggests that Cyclin A/CDK directly activates the Myb-MuvB (MMB) complex to induce transcription of a battery of genes required for mitosis, and that repression of CDK activity dampens this MMB mitotic transcriptome to promote endoreplication in both iECs and devECs. iECs and devECs differed, however, in that devECs had reduced expression of E2F1-dependent genes that function in S phase, whereas repression of the MMB transcriptome in iECs was sufficient to induce endoreplication without a reduction in S phase gene expression. Among the MMB regulated genes, knockdown of AurB protein and other subunits of the chromosomal passenger complex (CPC) induced endoreplication, as did knockdown of CPC-regulated cytokinetic, but not kinetochore, proteins. Together, our results indicate that the status of a CycA—Myb-MuvB—AurB network determines the decision to commit to mitosis or switch to endoreplication in both iECs and devECs, and suggest that regulation of different steps of this network may explain the known diversity of polyploid cycle types in development and disease.

Original languageEnglish (US)
Article numbere1008253
JournalPLoS Genetics
Volume15
Issue number7
DOIs
StatePublished - Jul 1 2019

Fingerprint

Endoreduplication
Cyclins
Polyploidy
cyclins
polyploidy
gene
protein
cells
integrated approach
transcriptome
interphase
mitosis
gene expression
S Phase
cancer
Transcriptome
Mitosis
genome
regeneration
kinetochores

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Rotelli, M. D., Policastro, R. A., Bolling, A. M., Killion, A. W., Weinberg, A. J., Dixon, M. J., ... Calvi, B. R. (2019). A Cyclin A—Myb-MuvB—Aurora B network regulates the choice between mitotic cycles and polyploid endoreplication cycles. PLoS Genetics, 15(7), [e1008253]. https://doi.org/10.1371/journal.pgen.1008253

A Cyclin A—Myb-MuvB—Aurora B network regulates the choice between mitotic cycles and polyploid endoreplication cycles. / Rotelli, Michael D.; Policastro, Robert A.; Bolling, Anna M.; Killion, Andrew W.; Weinberg, Abraham J.; Dixon, Michael J.; Zentner, Gabriel E.; Walczak, Claire; Lilly, Mary A.; Calvi, Brian R.

In: PLoS Genetics, Vol. 15, No. 7, e1008253, 01.07.2019.

Research output: Contribution to journalArticle

Rotelli, MD, Policastro, RA, Bolling, AM, Killion, AW, Weinberg, AJ, Dixon, MJ, Zentner, GE, Walczak, C, Lilly, MA & Calvi, BR 2019, 'A Cyclin A—Myb-MuvB—Aurora B network regulates the choice between mitotic cycles and polyploid endoreplication cycles', PLoS Genetics, vol. 15, no. 7, e1008253. https://doi.org/10.1371/journal.pgen.1008253
Rotelli, Michael D. ; Policastro, Robert A. ; Bolling, Anna M. ; Killion, Andrew W. ; Weinberg, Abraham J. ; Dixon, Michael J. ; Zentner, Gabriel E. ; Walczak, Claire ; Lilly, Mary A. ; Calvi, Brian R. / A Cyclin A—Myb-MuvB—Aurora B network regulates the choice between mitotic cycles and polyploid endoreplication cycles. In: PLoS Genetics. 2019 ; Vol. 15, No. 7.
@article{2fbdc9fecafa44b2a55bc939579b37b9,
title = "A Cyclin A—Myb-MuvB—Aurora B network regulates the choice between mitotic cycles and polyploid endoreplication cycles",
abstract = "Endoreplication is a cell cycle variant that entails cell growth and periodic genome duplication without cell division, and results in large, polyploid cells. Cells switch from mitotic cycles to endoreplication cycles during development, and also in response to conditional stimuli during wound healing, regeneration, aging, and cancer. In this study, we use integrated approaches in Drosophila to determine how mitotic cycles are remodeled into endoreplication cycles, and how similar this remodeling is between induced and developmental endoreplicating cells (iECs and devECs). Our evidence suggests that Cyclin A/CDK directly activates the Myb-MuvB (MMB) complex to induce transcription of a battery of genes required for mitosis, and that repression of CDK activity dampens this MMB mitotic transcriptome to promote endoreplication in both iECs and devECs. iECs and devECs differed, however, in that devECs had reduced expression of E2F1-dependent genes that function in S phase, whereas repression of the MMB transcriptome in iECs was sufficient to induce endoreplication without a reduction in S phase gene expression. Among the MMB regulated genes, knockdown of AurB protein and other subunits of the chromosomal passenger complex (CPC) induced endoreplication, as did knockdown of CPC-regulated cytokinetic, but not kinetochore, proteins. Together, our results indicate that the status of a CycA—Myb-MuvB—AurB network determines the decision to commit to mitosis or switch to endoreplication in both iECs and devECs, and suggest that regulation of different steps of this network may explain the known diversity of polyploid cycle types in development and disease.",
author = "Rotelli, {Michael D.} and Policastro, {Robert A.} and Bolling, {Anna M.} and Killion, {Andrew W.} and Weinberg, {Abraham J.} and Dixon, {Michael J.} and Zentner, {Gabriel E.} and Claire Walczak and Lilly, {Mary A.} and Calvi, {Brian R.}",
year = "2019",
month = "7",
day = "1",
doi = "10.1371/journal.pgen.1008253",
language = "English (US)",
volume = "15",
journal = "PLoS Genetics",
issn = "1553-7390",
publisher = "Public Library of Science",
number = "7",

}

TY - JOUR

T1 - A Cyclin A—Myb-MuvB—Aurora B network regulates the choice between mitotic cycles and polyploid endoreplication cycles

AU - Rotelli, Michael D.

AU - Policastro, Robert A.

AU - Bolling, Anna M.

AU - Killion, Andrew W.

AU - Weinberg, Abraham J.

AU - Dixon, Michael J.

AU - Zentner, Gabriel E.

AU - Walczak, Claire

AU - Lilly, Mary A.

AU - Calvi, Brian R.

PY - 2019/7/1

Y1 - 2019/7/1

N2 - Endoreplication is a cell cycle variant that entails cell growth and periodic genome duplication without cell division, and results in large, polyploid cells. Cells switch from mitotic cycles to endoreplication cycles during development, and also in response to conditional stimuli during wound healing, regeneration, aging, and cancer. In this study, we use integrated approaches in Drosophila to determine how mitotic cycles are remodeled into endoreplication cycles, and how similar this remodeling is between induced and developmental endoreplicating cells (iECs and devECs). Our evidence suggests that Cyclin A/CDK directly activates the Myb-MuvB (MMB) complex to induce transcription of a battery of genes required for mitosis, and that repression of CDK activity dampens this MMB mitotic transcriptome to promote endoreplication in both iECs and devECs. iECs and devECs differed, however, in that devECs had reduced expression of E2F1-dependent genes that function in S phase, whereas repression of the MMB transcriptome in iECs was sufficient to induce endoreplication without a reduction in S phase gene expression. Among the MMB regulated genes, knockdown of AurB protein and other subunits of the chromosomal passenger complex (CPC) induced endoreplication, as did knockdown of CPC-regulated cytokinetic, but not kinetochore, proteins. Together, our results indicate that the status of a CycA—Myb-MuvB—AurB network determines the decision to commit to mitosis or switch to endoreplication in both iECs and devECs, and suggest that regulation of different steps of this network may explain the known diversity of polyploid cycle types in development and disease.

AB - Endoreplication is a cell cycle variant that entails cell growth and periodic genome duplication without cell division, and results in large, polyploid cells. Cells switch from mitotic cycles to endoreplication cycles during development, and also in response to conditional stimuli during wound healing, regeneration, aging, and cancer. In this study, we use integrated approaches in Drosophila to determine how mitotic cycles are remodeled into endoreplication cycles, and how similar this remodeling is between induced and developmental endoreplicating cells (iECs and devECs). Our evidence suggests that Cyclin A/CDK directly activates the Myb-MuvB (MMB) complex to induce transcription of a battery of genes required for mitosis, and that repression of CDK activity dampens this MMB mitotic transcriptome to promote endoreplication in both iECs and devECs. iECs and devECs differed, however, in that devECs had reduced expression of E2F1-dependent genes that function in S phase, whereas repression of the MMB transcriptome in iECs was sufficient to induce endoreplication without a reduction in S phase gene expression. Among the MMB regulated genes, knockdown of AurB protein and other subunits of the chromosomal passenger complex (CPC) induced endoreplication, as did knockdown of CPC-regulated cytokinetic, but not kinetochore, proteins. Together, our results indicate that the status of a CycA—Myb-MuvB—AurB network determines the decision to commit to mitosis or switch to endoreplication in both iECs and devECs, and suggest that regulation of different steps of this network may explain the known diversity of polyploid cycle types in development and disease.

UR - http://www.scopus.com/inward/record.url?scp=85070183393&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85070183393&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1008253

DO - 10.1371/journal.pgen.1008253

M3 - Article

VL - 15

JO - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7390

IS - 7

M1 - e1008253

ER -