Proliferating Cell Nuclear Antigen-dependent Coordination of the Biological Functions of Human DNA Polymerase ?

Y-family DNA polymerases are believed to facilitate the replicative bypass of damaged DNA in a process commonly referred to as translesion synthesis. With the exception of DNA polymerase ? (pol?), which is defective in humans with the Xeroderma pigmentosum variant (XP-V) phenotype, little is known about the cellular function(s) of the remaining human Y-family DNA polymerases. We report here that an interaction between human DNA polymerase ? (pol?) and the proliferating cell nuclear antigen (PCNA) stimulates the processivity of pol? in a template-dependent manner in vitro. Mutations in one of the putative PCNA-binding motifs (PIP box) of pol? or the interdomain connector loop of PCNA diminish the binding between pol? and PCNA and concomitantly reduce PCNA-dependent stimulation of pol? activity. Furthermore, although retaining its capacity to interact with pol? in vivo, the pol?-PIP box mutant fails to accumulate in replication foci. Thus, PCNA, acting as both a scaffold and a modulator of the different activities involved in replication, appears to recruit and coordinate replicative and translesion DNA synthesis polymerases to ensure genome integrity.