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Published on: February 9, 2024
FAM190A deficiency creates a cell division defect
Kalpesh Patel1, Francesca Scrimieri, Soma Ghosh
1Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA.
Abstract:
Like the p16, SMAD4, and RB1 genes, FAM190A (alias CCSER1) lies at a consensus site of homogeneous genomic deletions in human cancer. FAM190A transcripts in 40% of cancers also contain in-frame deletions of evolutionarily conserved exons. Its gene function was unknown. We found an internal deletion of the FAM190A gene in a pancreatic cancer having prominent focal multinuclearity. The experimental knockdown of FAM190A expression by shRNA caused focal cytokinesis defects, multipolar mitosis, and multinuclearity as observed in time-lapse microscopy. FAM190A was localized to the γ-tubulin ring complex of early mitosis and to the midbody in late cytokinesis by immunofluorescence assay and was present in the nuclear fraction of unsynchronized cells by immunoblot. FAM190A interacted with EXOC1 and Ndel1, which function in cytoskeletal organization and the cell division cycle. Levels of FAM190A protein peaked 12 hours after release from thymidine block, corresponding to M-phase. Slower-migrating phosphorylated forms accumulated toward M-phase and disappeared after release from a mitotic block and before cytokinesis. Studies of FAM190A alterations may provide mechanistic insights into mitotic dysregulation and multinuclearity in cancer. We propose that FAM190A is a regulator or structural component required for normal mitosis and that both the rare truncating mutations and common in-frame deletion alteration of FAM190A may contribute to the chromosomal instability of cancer.
Insights
The FAM190A gene, often deleted in cancer, is crucial for normal cell division. Its disruption causes defects in mitosis and multinuclearity, contributing to cancer
Area of Science:
- Molecular Biology
- Cancer Genetics
- Cell Biology
Background:
- FAM190A (alias CCSER1) is located at a common genomic deletion site in human cancers.
- FAM190A transcripts frequently exhibit in-frame deletions of conserved exons in various cancers.
- The precise function of FAM190A in cellular processes remained largely unknown prior to this study.
Purpose of the Study:
- To elucidate the function of FAM190A in cell division and its potential role in cancer.
- To investigate the consequences of FAM190A alterations on mitosis and multinuclearity.
Main Methods:
- Analysis of FAM190A gene deletions in pancreatic cancer.
- Experimental knockdown of FAM190A expression using shRNA.
- Time-lapse microscopy to observe cell division.
- Immunofluorescence and immunoblot assays for protein localization and detection.
- Co-immunoprecipitation to identify interacting proteins.
Main Results:
- FAM190A knockdown induced focal cytokinesis defects, multipolar mitosis, and multinuclearity.
- FAM190A localizes to the gamma-tubulin ring complex during early mitosis and the midbody during cytokinesis.
- FAM190A interacts with EXOC1 and Ndel1, proteins involved in cytoskeletal organization and cell division.
- FAM190A protein levels peak during M-phase, with phosphorylated forms accumulating before cytokinesis.
Conclusions:
- FAM190A is essential for normal mitosis and cytokinesis.
- Disruptions in FAM190A, including deletions and mutations, can lead to mitotic dysregulation and multinuclearity in cancer.
- FAM190A alterations may contribute to chromosomal instability, a hallmark of cancer.
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