Nontraditional Roles of DNA Polymerase Eta Support Genome Duplication and Stability

DNA polymerase eta (Pol eta) 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 eta cellular functions in addition to DNA lesion bypass that are critical for maintaining genome stability. In vitro, Pol eta displays efficient DNA synthesis through difficult-to-replicate sequences, catalyzes D-loop extensions, and utilizes RNA-DNA hybrid templates. Human Pol eta is constitutively present at the replication fork. In response to replication stress, Pol eta is upregulated at the transcriptional and protein levels, and post-translational modifications regulate its localization to chromatin. Numerous studies show that Pol eta is required for efficient common fragile site replication and stability. Additionally, Pol eta can be recruited to stalled replication forks through protein-protein interactions, suggesting a broader role in replication fork recovery. During somatic hypermutations, Pol eta 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 eta to perform specialized functions during replication could promote genome stability by interrupting pure repeat arrays with base substitutions. Alternatively, not engaging Pol eta in genome duplication is costly, as the absence of Pol eta leads to incomplete replication and increased chromosomal instability.