On the role of p53 in the cellular response to aneuploidy

Akshay Narkar; Blake A Johnson; Pandurang Bharne; Jin Zhu; Veena Padmanaban; Debojyoti Biswas; Andrew Fraser; Pablo A Iglesias; Andrew J Ewald; Rong Li

doi:10.1016/j.celrep.2021.108892

On the role of p53 in the cellular response to aneuploidy

Cell Rep. 2021 Mar 23;34(12):108892. doi: 10.1016/j.celrep.2021.108892.

Authors

Affiliations

¹ Center for Cell Dynamics and Department of Cell Biology, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
² Center for Cell Dynamics and Department of Cell Biology, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA; Medical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ Center for Cell Dynamics and Department of Cell Biology, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
⁴ Electrical and Computer Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
⁵ Center for Cell Dynamics and Department of Cell Biology, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA; Electrical and Computer Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
⁶ Center for Cell Dynamics and Department of Cell Biology, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA; Department of Chemical and Biomolecular Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD 21205, USA; Mechanobiology Institute and Department of Biological Sciences, National University of Singapore, Singapore 117411, Singapore. Electronic address: rong@jhu.edu.

Abstract

Most solid tumors are aneuploid, and p53 has been implicated as the guardian of the euploid genome. Previous experiments using human cell lines showed that aneuploidy induction leads to p53 accumulation and p21-mediated G1 cell cycle arrest. We find that adherent 2-dimensional (2D) cultures of human immortalized or cancer cell lines activate p53 upon aneuploidy induction, whereas suspension cultures of a human lymphoid cell line undergo a p53-independent cell cycle arrest. Surprisingly, 3D human and mouse organotypic cultures from neural, intestinal, or mammary epithelial tissues do not activate p53 or arrest in G1 following aneuploidy induction. p53-deficient colon organoids have increased aneuploidy and frequent lagging chromosomes and multipolar spindles during mitosis. These data suggest that p53 may not act as a universal surveillance factor restricting the proliferation of aneuploid cells but instead helps directly or indirectly ensure faithful chromosome transmission likely by preventing polyploidization and influencing spindle mechanics.

Keywords: G1 arrest; aneuploidy; mitosis; organoids; p53.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aneuploidy*
Animals
Cell Adhesion
Cell Cycle Checkpoints
Cell Cycle Proteins / antagonists & inhibitors
Cell Cycle Proteins / metabolism
Cell Line
Colon / metabolism
Humans
Mammals
Mice
Mice, Inbred C57BL
Mitosis
Organoids / metabolism
Protein Serine-Threonine Kinases / antagonists & inhibitors
Protein Serine-Threonine Kinases / metabolism
Protein-Tyrosine Kinases / antagonists & inhibitors
Protein-Tyrosine Kinases / metabolism
Tumor Suppressor Protein p53 / metabolism*

Substances

Cell Cycle Proteins
Tumor Suppressor Protein p53
Protein-Tyrosine Kinases
Protein Serine-Threonine Kinases
TTK protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding