Translesion DNA Synthesis in Cancer: Molecular Mechanisms and Therapeutic Opportunities

Abstract

The genomic landscape of cancer is one marred by instability, but the mechanisms that underlie these alterations are multifaceted and remain a topic of intense research. Cellular responses to DNA damage and/or replication stress can affect genome stability in tumors and influence the response of patients to therapy. In addition to direct repair, DNA damage tolerance (DDT) is an element of genomic maintenance programs that contributes to the etiology of several types of cancer. DDT mechanisms primarily act to resolve replication stress, and this can influence the effectiveness of genotoxic drugs. Translesion DNA synthesis (TLS) is an important component of DDT that facilitates direct bypass of DNA adducts and other barriers to replication. The central role of TLS in the bypass of drug-induced DNA lesions, the promotion of tumor heterogeneity, and the involvement of these enzymes in the maintenance of the cancer stem cell niche presents an opportunity to leverage inhibition of TLS as a way of improving existing therapies. In the review that follows, we summarize mechanisms of DDT, misregulation of TLS in cancer, and discuss the potential for targeting these pathways as a means of improving cancer therapies.

Virtual Pharmacophore Screening Identifies Small‐Molecule Inhibitors of the Rev1‐CT/RIR Protein–Protein Interaction

“…[1][2][3] While this mechanism is responsible for rescuing cells during activer eplication, it does so at the expense of an increased mutationr ate in the surviving cells. [3,6,7] In the context of cancert reatment, TLS promotes tumor cell survival in the presence of first-line genotoxic chemotherapies, which can ultimately lead to acquired resistance to the first-line therapy. [3,6,7] In the context of cancert reatment, TLS promotes tumor cell survival in the presence of first-line genotoxic chemotherapies, which can ultimately lead to acquired resistance to the first-line therapy.…”

“…[3,6,7] In the context of cancert reatment, TLS promotes tumor cell survival in the presence of first-line genotoxic chemotherapies, which can ultimately lead to acquired resistance to the first-line therapy. [3,6,7] Proper TLS function requires the concertede fforto fm ultiple DNA polymerases in complex with the DNA clamp PCNA to controlas eries of switching eventst hat ensure this mechanism is only recruited to rescue replication stalled at DNA lesions. [3,6,7] Proper TLS function requires the concertede fforto fm ultiple DNA polymerases in complex with the DNA clamp PCNA to controlas eries of switching eventst hat ensure this mechanism is only recruited to rescue replication stalled at DNA lesions.…”

“…[4,5] The role of TLS in promoting cell survival has resultedi ni ts emergencea s ap otential target for the development of an ew class of anticancer agents. [3,6,7] In the context of cancert reatment, TLS promotes tumor cell survival in the presence of first-line genotoxic chemotherapies, which can ultimately lead to acquired resistance to the first-line therapy. [4,5] Disruption of TLS can sensitize cancers to genotoxic agents and decrease mutagenesisi n tumors,s uggesting that combination therapy with aT LS inhibitor could enhancet he efficacy of first-line agents and prevent chemoresistance.…”

The role of double‐strand break repair, translesion synthesis, and interstrand crosslinks in colorectal cancer progression—clinicopathological data and survival

“…DDT mechanisms are mediated by Y‐family translesion DNA polymerases (such as pol κ, pol η, and pol θ), which bypass DNA adducts, imbalanced dNTP pools, and unusual template structures. As a consequence, to impede fork collapse and apoptosis due to unrepaired DSB, translesion DNA polymerases induce mutation . So far, although a number of investigations have focused on the role of MMR, NER, and BER genes in CRC, fewer studies have evaluated DSBR, DDT/TLS, and ICLR roles from the perspective of expression characteristics and prognostic roles in CRC …”

“…As a consequence, to impede fork collapse and apoptosis due to unrepaired DSB, translesion DNA polymerases induce mutation. 15,16 So far, although a number of investigations have focused on the role of MMR, NER, and BER genes in CRC, fewer studies have evaluated DSBR, DDT/TLS, and ICLR roles from the perspective of expression characteristics and prognostic roles in CRC. 10,[17][18][19][20] Thus, since tumor heterogeneity and genomic instability are hallmarks of CRC, to pinpoint a role for DSBR, DDT/TLS and ICLR may offer a better understanding of these features.…”