Primpol, also known as Primase and DNA-directed Polymerase, is an enzyme with both primase and polymerase activities. It is a key player in DNA damage tolerance mechanisms, which are crucial for ensuring the timely and faithful duplication of the genome in the face of DNA lesions from endogenous and exogenous sources. DNA replication forks often encounter obstacles due to these lesions, and Primpol allows replication to continue by repriming ahead of the lesions, creating new starting points for DNA synthesis. It operates in both the nucleus and mitochondria [1,2,4,5].

PRIMPOL-dependent repriming leads to the formation of ssDNA gaps, and studies have found that different post-replicative repair mechanisms fill these gaps at different stages of the cell cycle. In G2, a mechanism dependent on RAD18, PCNA monoubiquitination, and REV1 and POLζ translesion synthesis polymerases promotes gap filling, while in S phase, the E2-conjugating enzyme UBC13, the RAD51 recombinase, and REV1-POLζ are responsible for gap filling [3]. Also, activation of the KRAS oncogene induces replication stress, and under such stress, PrimPol is phosphorylated at Ser255 and promotes repriming to maintain fork progression and cell survival in an ATR/Chk1-dependent manner, though it also generates ssDNA gaps leading to genomic instability [6].

In conclusion, Primpol is essential for maintaining DNA replication fork progression and genome stability in the face of DNA damage. Its role in filling ssDNA gaps and responding to oncogene-induced replication stress highlights its importance in understanding the mechanisms underlying genome integrity and cancer development. The studies on Primpol-related processes contribute to the exploration of potential new targets for cancer therapy [1,2,3,6].