Ribosome specialization by cancer-associated ribosomal protein mutations: progress made and open questions.

Congenital mutations in ribosomal proteins (RPs) cause Diamond-Blackfan anaemia (DBA) syndrome. Whereas DBA patients suffer from anaemia and disease symptoms owing to a lack of cell proliferation (hypo-proliferation) early in life, they have a significantly elevated risk of developing cancer (a disease of hyper-proliferation) at a later age. The association between ribosome defects and cancer is further underscored by animal models in which heterozygous RP loss promotes tumourigenesis, as well as by a variety of somatic RP mutations that have been described in haematological and solid malignancies. As discussed in this article, we have gained deeper insight into molecular mechanisms by which RP mutations can be associated with hypo- followed by hyper-proliferation phenotypes. Factors such as oxidative stress and DNA damage, onco-ribosome specialization with hyper-translation of oncogenes and altered extra-ribosomal functions seem essential. However, many questions still remain and more research is needed to explore to what extent different cancer-associated RP mutations can structurally and functionally specialize ribosomes into onco-ribosomes, and what opportunities this can provide to develop innovative cancer therapies.This article is part of the discussion meeting issue 'Ribosome diversity and its impact on protein synthesis, development and disease'.