Prof. Tom (Thomas) Moss has been a member of the Department of Molecular Biology, Medical Biochemistry and Pathology (formally the Department of Biochemistry) at the Laval University School of Medicine since he was recruited from the University of Portsmouth (UK) in 1986. Concurrently, he became Principal Investigator (PI) in the Laval University Cancer Research Centre and is now PI in the St-Patrick Research Group in Basic Oncology and in the Division of Oncology of the Québec University Hospital Research Centre. Originally from Portsmouth, Southern England, Prof. Moss obtained a BSc (hon.) in Applied Physics and a Doctorate in Biophysics from the University of Portsmouth. He went on to study gene regulation at the Institute of Molecular Biology of Zürich University, before returning to Portsmouth as Senior Lecturer and establishing his first laboratory there. His career has been marked by many important discoveries starting in the late ‘70s and early ‘80s, and he is recognized as a leading international expert in his field. Prof. Moss has received several personal awards over the course of his career, including EMBO and Medical Research Council (MRC)-UK Fellowships and MRC-Canada and FRSQ Scholarships, and was nominated as Scientist of the MRC-Canada and as Research Director of the CNRS-France.
The ribosome, genetic diseases, and cancer
The ribosome is responsible for decoding our genetic material and is the cell’s sole means to make protein. It is also the largest “enzyme” known, hence the effort required to make the 3 to 4 million ribosomes in each human cell is a severe limitation to growth. To grow, cancer cells must increase their production of ribosomes, a process known as Ribosome Biogenesis, and this makes them metabolically vulnerable. Oncogenes such as MYC and RAS render cells sensitive to so-called Nucleolar Stress, a surveillance pathway that links decreased fidelity of Ribosome Biogenesis to the central tumour suppressor p53 (TP53), and this increases their sensitivity to cytotoxic drugs. Some new anticancer drugs take advantage of this, e.g. BMH21 and CX5461, and are now showing some promise in clinical settings. However, our data also suggests that several existing cytotoxic drugs, such as cisplatin already target Ribosome Biogenesis. Further, we have recently shown that a genetic block Ribosome Biogenesis causes highly penetrant, p53-independent cell death of cancer cells, while leaving normal cells unaffected. This strongly suggests that drug targeting of Ribosome Biogenesis will offer some important new cancer treatments in the future.
The ribosome is itself made up two-thirds of RNA and only one-third of protein. In humans, the ribosomal RNAs are produced from 400 genes that form megabase tandem arrays at the Nucleolus Organizer Regions (NORs) of the short arms of 5 acrocentric chromosomes. The transcription of these genes creates the nucleoli, the cell’s ribosome factories in each cell nucleus, and the size of these nucleoli is a reliable marker of aggressive tumours. Transcription of the ribosomal RNA genes generates the 47S precursor that is first assembled into pre-ribosomal particles, then processed into the mature RNAs and the subunits of the ribosome. This process of Ribosome Biogenesis involves several hundred small non-coding RNAs and many hundreds of proteins. Mutations in the genes for these ribosomal proteins are responsible for a range of genetic diseases together known as Ribosomopathies, e.g. Diamond-Blackfan anemia (DBA), Dyskeratosis congenita (DC), etc. Ribosomal RNA genes are also involved in the chromosomal translocations that cause Down’s Syndrome, Uniparental Disomy, etc. These so-called “Robertsonian” translocations are also tightly linked to a range of cancers. One area of Dr. Moss’s work is to try to understand the role ribosomal RNA gene silencing plays in preventing these chromosomal translocations. Surprisingly, we discovered this silencing is completely absent in the earliest cells of the embryo, the Embryonic Stem Cells (ESCs), as well as in some cancer cells. We hypothesize that loss of ribosomal RNA gene silencing answers the enhanced metabolic needs of both embryonic and precancerous cells, but also increases the genome instability that drives the evolution of cancer. We are seeking ways to test this experimentally and hence to understand how normal cells are subverted in cancer, as well as the role that cancer stem cells play in this process.
9, rue McMahon
1744-3
Québec, Québec
Canada G1R 2J6
- Hamed-Abdelouahab, MeriemInternCHUL+1 418-525-4444, extension 42296meriem.hamed-abdelouahab.1@ulaval.ca
2705, boulevard Laurier
T4-50
Québec, QC
Canada G1V 4G2 - Lessard, FrédéricEmployeeL'Hôtel-Dieu de Québec+1 418-525-4444, extension 16930+1 418-525-4444, extension 16939+1 418-691-5439frederic.lessard@crchudequebec.ulaval.ca
9 rue McMahon
16939
Québec, QC
Canada G1R 3S3 - Sabourin-Félix, MarianneEmployeeL'Hôtel-Dieu de Québec+1 418-525-4444, extension 15304+1 418-649-0252, extension 66024+1 418-649-5406marianne.sabourin-felix.1@ulaval.camarianne.sabourin-felix@crchudequebec.ulaval.ca
9 rue McMahon
1744
Québec, QC
Canada G1R 3S3
TTF1 control of LncRNA synthesis delineates a tumor suppressor pathway directly regulating the ribosomal RNA genes
Journal ArticleJ Cell Physiol, 239 (8), 2024.
The fragile X proteins' enigma: to be or not to be nucleolar
Journal ArticleFront Cell Dev Biol, 12 , 2024.
HMG-boxes, ribosomopathies and neurodegenerative disease
Journal ArticleFront Genet, 14 , 2023.
Transcription factor UBF depletion in mouse cells results in downregulation of both downstream and upstream elements of the rRNA transcription network
Journal ArticleJ Biol Chem, 299 (10), 2023.
The human RNA polymerase I structure reveals an HMG-like docking domain specific to metazoans
Journal ArticleLife Sci Alliance, 5 (11), 2022.
Ribosomal DNA promoter recognition is determined in vivo by cooperation between UBTF1 and SL1 and is compromised in the UBTF-E210K neuroregression syndrome
Journal ArticlePLoS Genet, 18 (2), 2022.
Behavioral and molecular effects of Ubtf knockout and knockdown in mice
Journal ArticleBrain Res, 1793 , 2022.
Control of ribosomal RNA synthesis by hematopoietic transcription factors
Journal ArticleMol Cell, 82 (20), 2022.
The human RNA polymerase I structure reveals an HMG-like docking domain specific to metazoans
Journal ArticleLife Sci Alliance, 5 (11), 2022.
The chemotherapeutic agent CX-5461 irreversibly blocks RNA polymerase I initiation and promoter release to cause nucleolar disruption, DNA damage and cell inviability
Journal ArticleNAR Cancer, 2 (4), 2020.
Active projects
- Mechanism of Ribosomal RNA Gene Silencing and Its Roles in Pluripotency and Cancer, from 2017-04-01 to 2025-03-31
- The Ribosomal RNA Genes in Growth, Pluripotency, Senescence and Cancer, from 2024-03-01 to 2025-02-28
Recently finished projects
- Pathobiology and treatment of the UBTF E210K neuroregression syndrome, from 2021-07-01 to 2023-08-30
- Role of Misshappen (NIK/Msn) kinases and Extended-Synaptotagmins (E-Syts) in Wnt and FGF intracellular signaling pathways., from 2017-04-01 to 2023-03-31