Pole3-KO Mouse

POLE3, also known as DPB4/YBL1/CHRAC17, is one of the subunits of DNA polymerase ε. It contains a histone-like domain and is involved in multiple biological processes. POLE3 plays a role in chromatin-related functions, DNA repair, and replication-associated processes, which are crucial for maintaining genomic stability and cell-type-specific development [6,3,4].

Knockdown and knockout experiments have revealed that POLE3 is a transcriptional repressor of unintegrated HIV-1 DNA, maintaining it in a repressive chromatin state, which is important for efficient virus integration, escape from innate immune sensing, and optimal viral replication [1]. Loss of POLE3-POLE4 strongly sensitizes cancer cells to PARP inhibitors in a Polε level-independent manner, triggering replicative gap accumulation in a PRIMPOL-dependent manner [2]. POLE3 interacts with CHRAC1 to promote DNA repair, and its transcription is sensitive to the deposition of H2BK120ub1 and H3K79me2 [3]. Cells deficient in POLE3 show compromised H3K9me3 asymmetry and increased LINE expression [5]. Mice lacking Pole3 survive up to late embryonic stages, and hypomorphic and neomorphic alleles reveal a stage-specific function of Pole3 during T and B cell development [7].

In conclusion, POLE3 is essential for maintaining chromatin integrity, DNA repair, and replication-related processes. Its role in transcriptional repression of unintegrated HIV-1 DNA and sensitivity to PARP inhibitors in cancer cells, as well as its function in lymphocyte development, indicates its significance in both viral-host interactions and cancer-related research. Studies using gene knockout models have been instrumental in uncovering these functions, providing valuable insights into potential therapeutic targets for treating viral infections and cancers.