POLE3, also known as DPB4/YBL1/CHRAC17, is a subunit of DNA polymerase epsilon. It contains a histone-like domain and is involved in multiple essential biological functions. POLE3 is crucial for processes like DNA replication, chromatin integrity maintenance, and is associated with pathways related to histone modification and DNA damage repair [5,6]. Its biological importance extends to maintaining genomic stability and cell-type-specific functions, with implications in development and disease [7]. Genetic models, such as knockout mouse models, are valuable for studying POLE3's functions.

Loss-of-function experiments have revealed multiple key roles of POLE3. In HIV-1 replication, knockdown and knockout experiments showed that POLE3 is a transcriptional repressor of unintegrated HIV-1 DNA. It maintains unintegrated HIV-1 DNA in a repressive chromatin state, affecting virus integration efficiency and escape from innate immune sensing [1]. In cancer research, loss of POLE3-POLE4 complex sensitizes cancer cells to PARP inhibitors. This is not due to homologous recombination defects but rather triggers replicative gap accumulation in a PRIMPOL-dependent manner [2,4]. Also, POLE3 is involved in DNA double-strand breaks repair. WDR70 promotes H2BK120ub1, and deposition of related histone modifications in POLE3 loci is sensitive to its transcription. POLE3 interacts with CHRAC1 to promote DNA repair, and a CHRAC1 mutation in colorectal cancer leads to DNA repair defects [3].

In conclusion, POLE3 plays essential roles in DNA-related biological processes, including replication, repair, and chromatin-associated functions. Model-based research, especially KO/CKO mouse models, has provided insights into its functions in diseases such as viral infections and cancer. Understanding POLE3 can potentially contribute to developing new strategies for treating these diseases.