Ribosomal Genes Mutations in Cancer

Introduction to Ribosomal Genes Mutations

The ribosome is a complex cellular machine that is responsible for protein synthesis. Ribosome biogenesis is the process involving a series of assembly and maturation factors. In the past decades, studies have shown that ribosomal protein gene mutations can be detected in various cancer types, including endometrial cancer, T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, colorectal cancer, and glioma. What’s more, patients with diamond-blackfan anemia caused by mutated ribosomal proteins have a higher risk of leukemia or solid tumors. Through different experimental models, we can know that dysregulation of the p53 tumor suppressor network and altered mRNA translation may be the underlying mechanisms of cancer development. The advent of ribosome biology has provided an important field for cancer research.

Fig.1 The 5S RNP complex (RPL5, RPL11, and 5S rRNA) regulates MDM2-p53 in response to cellular stress. (Goudarzi, 2016)

Ribosomal Genes Mutations in Various Organisms

Mutations in the gene encoding ribosomal proteins have been found in a variety of organisms, including Drosophila, zebrafish, and humans. Minutes are a class of Drosophila mutants whose genes normally encode ribosomal proteins resulting in characteristic phenotypes such as reduced body size. Rps6 (eS6) mutant larvae have increased the growth and proliferation of lymph gland cells, suggesting that Rps6 has a tumor suppressor function. In the zebrafish model, malignant peripheral nerve sheet tumors (MPNSTs) are sarcomas that arise from peripheral nerves or cells associated with the nerve sheath. Studies have shown that zebrafish carrying heterozygous mutations in 17 different ribosomal protein genes are prone to MPNST. Notably, there have not been many reports of increased tumor incidence in mice harboring ribosomal protein mutations or deletions (e.g., Rps19, Rpl24, and Rps6).

In humans, ribosomopathies refer to congenital diseases that are related to genetic defects in ribosomal biogenesis factors and ribosomal proteins. Diamond-Blackfan anemia (DBA) is a dominant autosomal bone marrow failure syndrome associated with ribosomal protein genes mutation, including RPS19(eS19), RPS17(eS17), RPS24(eS24), RPL35A(eL33), etc. Dyskeratosis congenital (DKC) is a disease caused by gene mutations in DKC1.

Tumor Types with Ribosomal Genes Mutations

• GBM, T-ALL, lung-adenocarcinoma: RPL5 (uL18)
• Colorectal cancer: RPS20 (uS10)
• Chronic lymphocytic leukemia (CLL): RPS15(uS19)
• Gastric cancer, T-ALL, endometrial, colorectal cancer: RPL22 (eL22)
• T-ALL: RPL10 (uL16), RPL11(uL5)

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Reference

1. Goudarzi, K.; LINDSTRöM, M. Role of ribosomal protein mutations in tumor development. International journal of oncology. 2016, 48(4): 1313-1324.