Human TLS DNA polymerase: saviors or threats under replication stress?

The maintenance of genomic stability is crucial for life, threatened by DNA damage from both endogenous and exogenous sources. Cells employ DNA damage response through various repair mechanisms and DNA damage tolerance via translesion synthesis (TLS), to bypass DNA lesions and prevent replication fork collapse. This review explores the roles of human TLS polymerases in navigating replication stress, a critical process that can lead to genomic instability and cancer. It discusses TLS polymerase's dual role in genome preservation under certain physiological conditions while may also contribute to adaptive mutagenesis, highlighting their significance in DNA damage tolerance, somatic hypermutations, and cancer therapeutics. Understanding these mechanisms offers insights for developing targeted cancer therapies.