Fig. 6: TP53 and the nucleolar surveillance pathway as targets for convergent somatic mutation.

a Defective germline ribosome assembly in SDS promotes nucleolar stress through inhibitory binding of the 5S RNP complex (consisting of the 5S rRNA, uL5, encoded by RPL11 and uL18, encoded by RPL5) to the nuclear E3 ligase HDM2 (enhanced by eL22, encoded by RPL22), promoting p53 accumulation and apoptosis²². b Convergent evolution of somatic mutations restores ribosome homoeostasis, favouring HDM2-dependent p53 ubiquitination and degradation, through multiple independent somatic genetic rescue events including: (1) increased dose of SBDS or EFL1 proteins (2) reduced eIF6 dosage or eIF6 binding to the 60S subunit; (3) disrupted inhibitory binding of HDM2 to p53 through mutations in RPL5 and RPL22 ⁵⁰; (4) TP53 mutations. Ub ubiquitin.