Abstract
DNA lesions arising from both exogenous and endogenous sources occur frequently in DNA. During DNA replication, the presence of unrepaired DNA damage in the template can arrest replication fork progression, leading to fork collapse, double-strand break formation, and to genome instability. To facilitate completion of replication and prevent the generation of strand breaks, DNA damage tolerance (DDT) pathways play a key role in allowing replication to proceed in the presence of lesions in the template. The two main DDT pathways are translesion synthesis (TLS), which involves the recruitment of specialized TLS polymerases to the site of replication arrest to bypass lesions, and homology-directed damage tolerance, which includes the template switching and fork reversal pathways. With some exceptions, lesion bypass by TLS polymerases is a source of mutagenesis, potentially contributing to the development of cancer. The capacity of TLS polymerases to bypass replication-blocking lesions induced by anti-cancer drugs such as cisplatin can also contribute to tumor chemoresistance. On the other hand, during homology-directed DDT the nascent sister strand is transiently utilised as a template for replication, allowing for error-free lesion bypass. Given the role of DNA damage tolerance pathways in replication, mutagenesis and chemoresistance, a more complete understanding of these pathways can provide avenues for therapeutic exploitation. A number of small molecule inhibitors of TLS polymerase activity have been identified that show synergy with conventional chemotherapeutic agents in killing cancer cells. In this review, we will summarize the major DDT pathways, explore the relationship between damage tolerance and carcinogenesis, and discuss the potential of targeting TLS polymerases as a therapeutic approach.
Highlights
It is estimated that up to 50,000 DNA lesions can occur per cell in a single day, an average of around 2,000 DNA lesions per cell per hour [1]
The present review provides an overview of the main DNA damage tolerance (DDT) pathways in human cells, and discusses recent advances in targeting these pathways to develop cancer therapeutics
The two DDT pathways diverge, with monoubiquitination of proliferating cell nuclear antigen (PCNA) on K164 resulting in the induction of translesion synthesis (TLS), while polyubiquitination at K164 leads to homology-directed DDT (Figure 2)
Summary
It is estimated that up to 50,000 DNA lesions can occur per cell in a single day, an average of around 2,000 DNA lesions per cell per hour [1]. While the majority of DNA damage is removed by repair pathways, including nucleotide excision repair and base excision repair, prior to cells entering S-phase, lesions can remain in the DNA template during DNA replication. The main DNA polymerases that carry out genomic DNA replication, polymerase d (Pol d) on the lagging strand and polymerase ε (Pol ε) on the leading strand, can both be blocked by DNA damage in the template strand, leading to replication fork stalling, fork collapse, chromosome breakage and genomic instability. To resolve this problem, DNA damage tolerance (DDT) pathways that allow replication of damaged DNA to continue while reducing genomic instability, are present in virtually all organisms [1,2,3,4]
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