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Review
. 2023 Feb 1;37(3-4):72-73.
doi: 10.1101/gad.350527.123. Epub 2023 Feb 22.

The evolving tale of Pol2 function

Matthew Gallitto  1 , Zhiguo Zhang  2
Affiliations
Review

The evolving tale of Pol2 function

Matthew Gallitto et al. Genes Dev. .

Abstract

DNA replication is complex and highly regulated, and DNA replication errors can lead to human diseases such as cancer. DNA polymerase ε (polε) is a key player in DNA replication and contains a large subunit called POLE, which possesses both a DNA polymerase domain and a 3'-5' exonuclease domain (EXO). Mutations at the EXO domain and other missense mutations on POLE with unknown significance have been detected in a variety of human cancers. Based on cancer genome databases, Meng and colleagues (pp. 74-79) previously identified several missense mutations in POPS (pol2 family-specific catalytic core peripheral subdomain), and mutations at the conserved residues of yeast Pol2 (pol2-REL) showed reduced DNA synthesis and growth. In this issue of Genes & Development, Meng and colleagues (pp. 74-79) found unexpectedly that mutations at the EXO domain rescue the growth defects of pol2-REL. They further discovered that EXO-mediated polymerase backtracking impedes forward movement of the enzyme when POPS is defective, revealing a novel interplay between the EXO domain and POPS of Pol2 for efficient DNA synthesis. Additional molecular insight into this interplay will likely inform the impact of cancer-associated mutations found in both the EXO domain and POPS on tumorigenesis and uncover future novel therapeutic strategies.

Keywords: EXO domain; Pol2; replication elongation; sister fork asymmetry.

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