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

• Published in: PLoS genetics Vol. 15; no. 7; p. e1008253
• Main Authors: Rotelli, Michael D, Policastro, Robert A, Bolling, Anna M, Killion, Andrew W, Weinberg, Abraham J, Dixon, Michael J, Zentner, Gabriel E, Walczak, Claire E, Lilly, Mary A, Calvi, Brian R
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-07-2019; Public Library of Science (PLoS)
• Subjects: Aging; Animals; Aurora B protein; Aurora Kinase B - metabolism; Bioinformatics; Biology; Biology and Life Sciences; Cancer; Cell cycle; Cell Cycle Proteins - metabolism; Cell division; Control; Cyclin A; Cyclin A - metabolism; Cyclin-dependent kinase; Deoxyribonucleic acid; DNA; Drosophila - genetics; Drosophila - metabolism; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Endoreduplication; Female; Gene expression; Gene Expression Profiling; Genetic aspects; Genomes; Insects; Interactomes; Kinases; Mitosis; Polyploidy; Protein research; Proto-Oncogene Proteins c-myb - metabolism; Research and Analysis Methods; S phase; Software; Supervision; Tissue engineering; Transcription; Wound healing; United States; Indiana; United States > US; Indianapolis Indiana
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1008253

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.