Lysine demethylase <scp>4A</scp> is a centrosome‐associated protein required for centrosome integrity and genomic stability
Centrosomes play a fundamental role in nucleating and organizing microtubules in the cell and are vital for faithful chromosome segregation and maintenance of genomic stability. Loss of structural or functional integrity of centrosomes causes genomic instability and is a driver of oncogenesis. Here we identify lysine demethylase 4A (KDM4A), an epigenetic 'eraser' of chromatin methyl marks, as a centrosome-localized protein, visualized at the nanometer-scale resolution. We additionally uncovered that KDM4A demethylase enzymatic activity is required to maintain centrosome homeostasis and integrity; a previously unknown functionality unlinked to altered expression of genes regulating centrosome number. We find that KDM4A interacts with and localizes to the centrosome in all stages of mitosis, where it maintains centrosome numbers and centriole engagement during mitosis. Loss of KDM4A results in supernumerary centrosomes and accrual of chromosome segregation errors including chromatin bridges and micronuclei, markers of genomic instability. In summary, these data highlight a previously unknown role for an epigenetic 'eraser' regulating centrosome integrity, mitotic fidelity, and genomic stability at the centrosome.
Authors
- Anna‐Karin Gustavsson (ORCID: https://orcid.org/0000-0002-0980-1168)
- Dereck Mezquita (ORCID: https://orcid.org/0000-0002-9307-6762)
- Ashley Boice
- Sofía Vargas-Hernández (ORCID: https://orcid.org/0000-0002-8726-7298)
- Yuya Nakatani (ORCID: https://orcid.org/0000-0002-1289-3921)
- Pratim Chowdhury (ORCID: https://orcid.org/0009-0003-8051-6153)
- Richard I. Han (ORCID: https://orcid.org/0000-0002-8332-622X)
- Cristian Coarfa (ORCID: https://orcid.org/0000-0002-4183-4939)
- Claude Chew
- Sandra L. Grimm (ORCID: https://orcid.org/0000-0002-0682-3134)
- Julia F. Love (ORCID: https://orcid.org/0000-0001-6642-6301)
- Frank M. Mason (ORCID: https://orcid.org/0000-0003-1338-494X)
- Ruhee Dere (ORCID: https://orcid.org/0000-0002-1457-609X)
- Manga Motrapu (ORCID: https://orcid.org/0000-0001-9579-4066)
- Xiaoli Wang (ORCID: https://orcid.org/0000-0002-7198-273X)
- Elisabeth D. Martínez (ORCID: https://orcid.org/0000-0003-1131-3689)
- Cheryl L. Walker (ORCID: https://orcid.org/0000-0001-5787-6423)
Institutions
- The University of Texas MD Anderson Cancer Center (US)
- Baylor College of Medicine (US)
- Southwestern Medical Center (US)
- Children's Cancer Center (US)
- Rice University (US)
- The University of Texas Southwestern Medical Center (US)
- Vanderbilt University Medical Center (US)
Publication Details
- Journal
- FEBS Journal
- Published
- 2025-08-28
- DOI
- https://doi.org/10.1111/febs.70240
- Citations
- 1
- Primary Topic
- Microtubule and mitosis dynamics
- Type
- article
- Field-Weighted Citation Impact
- 1.15
Funders
- U.S. Department of Defense
- Welch Foundation
- Cancer Prevention and Research Institute of Texas
- Rice University
- National Institutes of Health
- National Institute of Mental Health
- National Cancer Institute
- National Institute of General Medical Sciences
- National Institute of Environmental Health Sciences
- National Institute on Minority Health and Health Disparities
- Congressionally Directed Medical Research Programs