The deacetylation-phosphorylation regulation of SIRT2-SMC1A axis as a mechanism of antimitotic catastrophe in early tumorigenesis
Open Access
- 26 February 2021
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Advances
- Vol. 7 (9), eabe5518
- https://doi.org/10.1126/sciadv.abe5518
Abstract
Improper distribution of chromosomes during mitosis can contribute to malignant transformation. Higher eukaryotes have evolved a mitotic catastrophe mechanism for eliminating mitosis-incompetent cells; however, the signaling cascade and its epigenetic regulation are poorly understood. Our analyses of human cancerous tissue revealed that the NAD-dependent deacetylase SIRT2 is up-regulated in early-stage carcinomas of various organs. Mass spectrometry analysis revealed that SIRT2 interacts with and deacetylates the structural maintenance of chromosomes protein 1 (SMC1A), which then promotes SMC1A phosphorylation to properly drive mitosis. We have further demonstrated that inhibition of SIRT2 activity or continuously increasing SMC1A-K579 acetylation causes abnormal chromosome segregation, which, in turn, induces mitotic catastrophe in cancer cells and enhances their vulnerability to chemotherapeutic agents. These findings suggest that regulation of the SIRT2-SMC1A axis through deacetylation-phosphorylation permits escape from mitotic catastrophe, thus allowing early precursor lesions to overcome oncogenic stress.This publication has 66 references indexed in Scilit:
- Role of SMC1 in Overcoming Drug Resistance in Triple Negative Breast CancerPLOS ONE, 2013
- HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycleNature, 2012
- SIRT2 Maintains Genome Integrity and Suppresses Tumorigenesis through Regulating APC/C ActivityCancer Cell, 2011
- Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012Cell Death & Differentiation, 2011
- The cohesin complex is required for the DNA damage-induced G2/M checkpoint in mammalian cellsThe EMBO Journal, 2009
- Cohesin subunit SMC1 associates with mitotic microtubules at the spindle poleProceedings of the National Academy of Sciences of the United States of America, 2008
- Lysine Acetylation: Codified Crosstalk with Other Posttranslational ModificationsMolecular Cell, 2008
- Chromatid cohesion defects may underlie chromosome instability in human colorectal cancersProceedings of the National Academy of Sciences of the United States of America, 2008
- Sirtuins: critical regulators at the crossroads between cancer and agingOncogene, 2007
- Cell death by mitotic catastrophe: a molecular definitionOncogene, 2004