Figure 2. RNA polymerase III involvement in disease.

a ∣ Structure of RNA polymerase III (Pol III) (Protein Data Bank entry 7AST)²³. The colours identify Pol III subunits that harbour pathological mutations in humans. b ∣ The regulatory effect of oncoproteins (red) and tumour suppressors (yellow) on Pol III-mediated transcription of tRNA genes. The three subunits of TFIIIB: TATA-box-binding protein (TBP), B double prime 1 (BDP1), and B-related factor-1 (BRF1), are shown interacting with TFIIIC. mTORC1 indirectly stimulates Pol III transcription via inhibition of MAF1, a negative regulator of Pol III. Ras small GTPases activate their downstream effector extracellular signal-regulated kinase (ERK), which induces BRF1 expression. Rb binds directly to BRF1, which inhibits Pol III recruitment. NOTCH1 stimulates tRNA^Val transcription both directly and via targeting MYC. MYC directly interacts with BRF1 and activates the histone-modifying enzymes transformation and transcription domain-associated protein (TRRAP) and GCN5. P53 directly inhibits TBP and Pol III recruitment. Part a is adapted from ref²³.