The importance of an interaction network for proper DNA polymerase ζ heterotetramer activity

Precisely controlled mechanisms have been evolved to rescue impeded DNA replication resulting from encountered obstacles and involve a set of low-fidelity translesion synthesis (TLS) DNA polymerases. Studies in recent years have brought new insights into those TLS polymerases, especially concerning the structure and subunit composition of DNA polymerase zeta (Pol ζ). Pol ζ is predominantly involved in induced mutagenesis as well as the bypass of noncanonical DNA structures, and it is proficient in extending from terminal mismatched nucleotides incorporated by major replicative DNA polymerases. Two active forms of Pol ζ, heterodimeric (Pol ζ₂) and heterotetrameric (Pol ζ₄) ones, have been identified and studied. Here, in the light of recent publications regarding induced and spontaneous mutagenesis and diverse interactions within Pol ζ holoenzyme, combined with Pol ζ binding to the TLS polymerase Rev1p, we discuss the subunit composition of Pol ζ in various cellular physiological conditions. Available data show that it is the heterotetrameric form of Pol ζ that is involved both during spontaneous and induced mutagenesis, and underline the importance of interactions within Pol ζ when an increased Pol ζ recruitment occurs. Understanding Pol ζ function in the bypass of DNA obstacles would give a significant insight into cellular tolerance of DNA damage, genetic instability and the onset of cancer progression.