Freedom to err: The expanding cellular functions of translesion DNA polymerases

Translesion synthesis (TLS) DNA polymerases were originally described as error-prone enzymes involved in the bypass of DNA lesions. However, extensive research over the past few decades has revealed that these enzymes play pivotal roles not only in lesion bypass, but also in a myriad of other cellular processes. Such processes include DNA replication, DNA repair, epigenetics, immune signaling, and even viral infection. This review discusses the wide range of functions exhibited by TLS polymerases, including their underlying biochemical mechanisms and associated mutagenicity. Given their multitasking ability to alleviate replication stress, TLS polymerases represent a cellular dependency and a critical vulnerability of cancer cells. Hence, this review also highlights current and emerging strategies for targeting TLS polymerases in cancer therapy.

Automated summary

TLS polymerases, originally known for their error-prone functions in bypassing DNA lesions, have been found to play pivotal roles in various cellular processes. Besides lesion bypass, these enzymes are involved in DNA replication, DNA repair, epigenetics, immune signaling, and viral infection. Due to their multitasking ability to alleviate replication stress, TLS polymerases are both a cellular dependency and a critical vulnerability of cancer cells. This review highlights the current and emerging strategies for targeting TLS polymerases in cancer therapy.