Regulation of translesion DNA synthesis in mammalian cells

Abstract

The genomes of all living cells are under endogenous and exogenous attacks every day, causing diverse genomic lesions. Most of the lesions can be timely repaired by multiple DNA repair pathways. However, some may persist during S‐phase, block DNA replication, and challenge genome integrity. Eukaryotic cells have evolved DNA damage tolerance (DDT) to mitigate the lethal effects of arrested DNA replication without prior removal of the offending DNA damage. As one important mode of DDT, translesion DNA synthesis (TLS) utilizes multiple low‐fidelity DNA polymerases to incorporate nucleotides opposite DNA lesions to maintain genome integrity. Three different mechanisms have been proposed to regulate the polymerase switching between high‐fidelity DNA polymerases in the replicative machinery and one or more specialized enzymes. Additionally, it is known that proliferating cell nuclear antigen (PCNA) mono‐ubiquitination is essential for optimal TLS. Given its error‐prone property, TLS is closely associated with spontaneous and drug‐induced mutations in cells, which can potentially lead to tumorigenesis and chemotherapy resistance. Therefore, TLS process must be tightly modulated to avoid unwanted mutagenesis. In this review, we will focus on polymerase switching and PCNA mono‐ubiquitination, the two key events in TLS pathway in mammalian cells, and summarize current understandings of regulation of TLS process at the levels of protein–protein interactions, post‐translational modifications as well as transcription and noncoding RNAs. Environ. Mol. Mutagen. 61:680–692, 2020. © 2020 Wiley Periodicals, Inc.

Transient activation of tumoral DNA damage tolerance pathway coupled with immune checkpoint blockade exerts durable tumor regression in mouse melanoma

“…Based on these observations, we sought to devise therapeutic strategy to increase neoantigens in solid tumors. We have developed an experimental model that utilizes precisely dosed and timed intratumoral administration of the DNA‐damaging drug, cisplatin, which we titrated not to kill tumor cells, but instead inhibit DNA replication catalyzed by high‐fidelity DNA polymerases and activate the DNA damage tolerance pathway (Hashimoto et al, 2017; Ma et al, 2020; Waters et al, 2009), thereby shifting synthesis to error‐prone translesion synthesis (TLS) DNA polymerases (Ghosal & Chen, 2013; Sale et al, 2012; Waters et al, 2009). TLS polymerases‐catalyzed DNA synthesis is predicted to increase the tumor mutation burden and thereby augment tumoral immunogenicity.…”

Targeting translesion synthesis (TLS) to expose replication gaps, a unique cancer vulnerability

“…While most TLS-centric reviews provide a comprehensive analysis of multiple functions of TLS polymerases [46,75,140,141], the newly identified role for TLS in countering RS and suppressing replication gaps that arise behind the replication fork, is yet to be discussed [67]. Here, we review the function of TLS to blunt the RS-associated anticancer barrier and also to suppress ssDNA gap formation, and how these roles function as an important cancer adaptation during cancer evolution.…”

The Mitochondrial Response to DNA Damage

“…Trans- lesion synthesis (TLS) can bypass the DNA replication block caused by DNA damages ( Waters et al, 2009 ; Sale, 2013 ). It is an error-prone process, in which the polymerases with low fidelity are involved ( Ma X. et al, 2020 ). In TLS, nucleotides are incorporated to repair DNA lesions but convert them to DNA mutations.…”

“…It requires DNA polymerase selection and switching ( Friedberg et al, 2005 ). A group of specialized DNA polymerases termed TLS polymerases are utilized in this process, which are categorized into several families ( Sale, 2013 ; Ma X. et al, 2020 ). Rev1, Polκ, Polη, and Polι belong to the best characterized Y-family polymerases, while polymerase zeta (Polζ) is a B-family polymerase ( Yang and Gao, 2018 ).…”