Fig. 6.

Polε exonuclease domain alterations as a source of increased DNA polymerase activity and ultramutation in cancers. Synthesis by both wild-type Polε and exo⁻ Polε involves partitioning of the primer terminus between the polymerase (Pol) and exonuclease (Exo) active sites. This partitioning limits the rate of DNA synthesis and prevents efficient mismatch extension, leading to the correction of errors by the intrinsic (wild-type Polε) or extrinsic (exo⁻ Polε) mechanisms. In contrast, the cancer-associated P301R substitution restricts access of the primer terminus to the exonuclease site, prompting the polymerase to stay in the elongation mode and, thus, resulting in hyperactivity and a high mutation rate