Nontraditional Roles of DNA Polymerase Eta Support Genome Duplication and Stability

DNA polymerase eta (Pol η) is a Y-family polymerase and the product of the POLH gene. Autosomal recessive inheritance of POLH mutations is the cause of the xeroderma pigmentosum variant, a cancer predisposition syndrome. This review summarizes mounting evidence for expanded Pol η cellular functions in addition to DNA lesion bypass that are critical for maintaining genome stability. In vitro, Pol η displays efficient DNA synthesis through difficult-to-replicate sequences, catalyzes D-loop extensions, and utilizes RNA–DNA hybrid templates. Human Pol η is constitutively present at the replication fork. In response to replication stress, Pol η is upregulated at the transcriptional and protein levels, and post-translational modifications regulate its localization to chromatin. Numerous studies show that Pol η is required for efficient common fragile site replication and stability. Additionally, Pol η can be recruited to stalled replication forks through protein–protein interactions, suggesting a broader role in replication fork recovery. During somatic hypermutations, Pol η is recruited by mismatch repair proteins and is essential for V_H gene A:T basepair mutagenesis. Within the global context of repeat-dense genomes, the recruitment of Pol η to perform specialized functions during replication could promote genome stability by interrupting pure repeat arrays with base substitutions. Alternatively, not engaging Pol η in genome duplication is costly, as the absence of Pol η leads to incomplete replication and increased chromosomal instability.