The genes that control many aspects of cellular function are contained on chromosomes in the cell nucleus. If these genes or the chromosomes that carry them become damaged, many aspects of cell function can be altered. Gene and chromosome changes can cause birth defects, accumulate during aging, are found in nearly every cancer, and are thought to have many adverse effects on health. This proposal hypothesizes that a set of 80 genes, dispersed around the various chromosomes, are exploited to recognize cells with large-scale genetic changes and eliminate them before they affect health. These genes encode ribosomal proteins, each one of which assembles into a unique position in the ribosome, so that ribosome assembly is affected if any are limiting. Studies in the fruitfly Drosophila document a regulatory pathway that is activated by ribosomal protein gene imbalance and that leads to cell elimination by cell competition with nearby normal cells. One goal of this proposal is to verify that ribosomal protein genes, and the regulatory genes that respond to their imbalance, are able to target cells with genetic damage for competitive elimination, and to define the range of genome damage that is subject to this regulatory mechanism in somatic tissues. A second goal is to assess the role of cell competition in protecting the germline from aneuploid genetic changes that might lead to birth defects. These studies make use of targeted genetic recombination methods using fruitfly chromosomes. These studies will establish the importance and scope of a newly-recognized mechanism that can remove cells with large-scale genetic damage, and which may play an important role in the prevention of birth defects and of cancer, as well as in healthy aging and prevention of age-related diseases.
Aging, cancer and birth defects are all associated with large-scale genetic changes to the body?s cells. This project assesses the contribution of a cell competition process to the recognition and eliminated of altered cells by more normal cells. The goal is to help define how the impacts of deleterious genetic change on reproduction and aging are minimized.
|Kale, Abhijit; Ji, Zhejun; Kiparaki, Marianthi et al. (2018) Ribosomal Protein S12e Has a Distinct Function in Cell Competition. Dev Cell 44:42-55.e4|
|Kale, Abhijit; Baker, Nicholas E (2018) Tumor evolution: Multiple induction mechanisms for cell competition. Mol Cell Oncol 5:e1481812|
|Baker, Nicholas E (2017) Mechanisms of cell competition emerging from Drosophila studies. Curr Opin Cell Biol 48:40-46|
|Baker, Nicholas E; Kale, Abhijit (2016) Mutations in ribosomal proteins: Apoptosis, cell competition, and cancer. Mol Cell Oncol 3:e1029065|
|Kale, Abhijit; Rimesso, Gerard; Baker, Nicholas E (2016) Local Cell Death Changes the Orientation of Cell Division in the Developing Drosophila Wing Imaginal Disc Without Using Fat or Dachsous as Orienting Signals. PLoS One 11:e0167637|
|Lee, Chang-Hyun; Rimesso, Gerard; Reynolds, David M et al. (2016) Whole-Genome Sequencing and iPLEX MassARRAY Genotyping Map an EMS-Induced Mutation Affecting Cell Competition in Drosophila melanogaster. G3 (Bethesda) 6:3207-3217|
|Fullard, John F; Baker, Nicholas E (2015) Signaling by the engulfment receptor draper: a screen in Drosophila melanogaster implicates cytoskeletal regulators, Jun N-terminal Kinase, and Yorkie. Genetics 199:117-34|
|Kale, A; Li, W; Lee, C-H et al. (2015) Apoptotic mechanisms during competition of ribosomal protein mutant cells: roles of the initiator caspases Dronc and Dream/Strica. Cell Death Differ 22:1300-12|
|Baker, Nicholas E; Jenny, Andreas (2014) Metabolism and the other fat: a protocadherin in mitochondria. Cell 158:1240-1241|