Graphical Abstract.

Speculative model of early Xenopus embryo replisome. High Rad18 abundance induces both constitutive PCNA monoubiquitination (PCNA^mUb) and active translesion DNA synthesis (TLS) generating mutations (red triangles) at high rate (+ sign). Both Rad18 homology-directed repair activity (HDR) and the mismatch repair system (MMR) function synergistically with TLS to reduce the mutation load (− sign). The Rad18 residues important for TLS activity (C28) and HDR activity (C207) are also indicated.