Abstract

By extending synthesis opposite from a diverse array of DNA lesions, DNA polymerase (Pol) ζ performs a crucial role in translesion synthesis (TLS). In yeast and cancer cells, Rev1 functions as an indispensable scaffolding component of Polζ and it imposes highly error-prone TLS upon Polζ. However, for TLS that occurs during replication in normal human cells, Rev1 functions instead as a scaffolding component of Pols η, ι, and κ and Rev1-dependent TLS by these Pols operates in a predominantly error-free manner. The lack of Rev1 requirement for Polζ function in TLS in normal cells suggested that some other protein substitutes for this Rev1 role. Here, we identify a novel role of Polλ as an indispensable scaffolding component of Polζ. TLS studies opposite a number of DNA lesions support the conclusion that as an integral component, Polλ adapts Polζ-dependent TLS to operate in a predominantly error-free manner in human cells, essential for genome integrity and cellular homeostasis.

Highlights

  • DNA lesions that escape removal by excision repair processes block the progression of replication forks (RFs)

  • To analyze the role of Polλ in translesion synthesis (TLS), we used the SV40 duplex plasmid in which bidirectional replication initiates from an origin of replication and TLS through the DNA lesion carried on the template for leading or lagging strand replication is determined by the frequency of blue colonies among the total Kan+ colonies (Yoon et al, 2009, 2010b)

  • In other studies we have provided evidence that the Pols identified to have a role in TLS opposite UV lesions in plasmid studies are required for RF progression through UV lesions in primary cells (Yoon et al, 2019b)

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Summary

Introduction

DNA lesions that escape removal by excision repair processes block the progression of replication forks (RFs). By promoting proficient replication through DNA lesions, translesion synthesis (TLS) DNA polymerases (Pols) prevent the collapse of RFs stalled at DNA lesion sites and protect against chromosomal instability and tumorigenesis (Yoon et al, 2019b). Biochemical, structural, and genetic studies have indicated that TLS Pols have specialized functions in replicating through DNA lesions, and that their active sites are adapted for accommodating specific types of DNA lesions (Prakash et al, 2005). Biochemical studies have shown that Polζ functions in the extension step of TLS and is proficient in extending synthesis past a large variety of DNA lesions (Johnson et al, 2000a, 2001; Haracska et al, 2001; Nair et al, 2006)

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