The goal of this project is to elucidate mechanisms that protect the genetic integrity of individual cells. DNA damage that leads altered gene numbers in individual cells is very common in tumors, and contributes to their progression. Similar damage is thought to occur in many cells in the body over time. Indeed such damage may be a hallmark of the aging process and a contributor to age related diseases including dementia, cardiovascular disease and diabetes, in addition to cancer. By using Drosophila melanogaster mosaic animals that contain cells with differing genotypes to mimic genome alterations, the effects of such somatic genetic diversity can be studied experimentally. The project examines the hypothesis that imbalances in ribosomal protein genes can trigger a 'cell competition'response that removes them in favor or other, genetically-normal cells. The domains of particular ribosomal proteins that are responsible for this additional function, beyond the well-known role of ribosomal proteins in protein synthesis, will be established using structural and functional analysis of clones genes in vivo. Particular attention will be paid to th location within the cell where ribosomal proteins are important, and to the hypothesis that ribosomal protein imbalances activate tumor suppressors of the Salvador-Hippo-Warts pathway to promote elimination of damaged cells. Genetic screens will be conducted that will identify other components of the process, and seek to identify the molecular mechanisms whereby ribosomal protein imbalance leads to cell elimination.

Public Health Relevance

DNA damage that changes the overall gene complement of individual cells contributes to cancer and is thought to occur in aging, increasing the frequency of age-related diseases. This project investigates the mechanisms cells use to detect such genetic changes, and how individual damaged cells may then be recognized and removed.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM104213-02
Application #
8737295
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Reddy, Michael K
Project Start
2013-09-20
Project End
2017-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
City
Bronx
State
NY
Country
United States
Zip Code
10461
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
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
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
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