Role of Y-family translesion DNA polymerases in replication stress: Implications for new cancer therapeutic targets

Abstract

DNA replication stress, defined as the slowing or stalling of replication forks, is considered an emerging hallmark of cancer and a major contributor to genomic instability associated with tumorigenesis [1]. Recent advances have been made in attempting to target DNA repair factors involved in alleviating replication stress to potentiate genotoxic treatments. Various inhibitors of ATR and Chk1, the two major kinases involved in the intra-S-phase checkpoint, are currently in Phase I and II clinical trials [2]. In addition, currently approved inhibitors of Poly-ADP Ribose Polymerase (PARP) show synthetic lethality in cells that lack double-strand break repair such as in BRCA½ deficient tumors [3]. These drugs have also been shown to exacerbate replication stress by creating a DNA-protein crosslink, termed PARP 'trapping', and this is now thought to contribute to the therapeutic efficacy. Translesion synthesis (TLS) is a mechanism whereby special repair DNA polymerases accommodate and tolerate various DNA lesions to allow for damage bypass and continuation of DNA replication [4]. This class of proteins is best characterized by the Y-family, encompassing DNA polymerases (Pols) Kappa, Eta, Iota, and Rev1. While best studied for their ability to bypass physical lesions in the DNA, there is accumulating evidence for these proteins in coping with various natural replication fork barriers and alleviating replication stress. In this mini-review, we will highlight some of these recent advances, and discuss why targeting the TLS pathway may be a mechanism of enhancing cancer associated replication stress. Exacerbation of replication stress can lead to increased genome instability, which can be toxic to cancer cells and represent a therapeutic vulnerability.

β-HPV 8E6 Attenuates ATM and ATR Signaling in Response to UV Damage

“…POLη (green) and nuclei stained (blue) with DAPI. Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 30 September 2019 doi:10.20944/preprints201909.0338.v1Figure suggests that β-HPV E6 reduces POLη expression[40,63]. This is supported by our immunoblot analysis that shows β-HPV 8E6 causes a sizable decrease in POLη(Figure 6A).…”

“…Specifically, β-HPV E6 reduces the ATR-dependent phosphorylation required for XPA stabilization and NER function [37,38]. β-HPV E6 also attenuates stabilization of POLη, the TLS polymerase most relevant for bypassing UV lesions [39,40]. Further, while β-HPV E6 decreases CHK1 phosphorylation and total CHK1 abundance, signaling events further downstream were not attenuated [41].…”

Targeting the DNA Damage Response for the Treatment of High Risk Neuroblastoma

“…In this pathway, errors in the newly synthesized strand are removed and the DNA is resynthesized by the replication machinery (112). Bulky abducts which remain unrepaired at DNA replication are bypassed by a process known as translesion synthesis (TLS), which allows restoration of the double stranded DNA prior to NER (113).…”

β-HPV 8E6 Attenuates ATM and ATR Signaling in Response to UV Damage

“…NER is responsible for physically removing UV-induced DNA lesions and it has been shown that an essential protein, XPA, is stabilized by ATR phosphorylation [37,38]. The TLS pathway helps bypass UV lesions primarily through the TLS polymerase, POLη, which is regulated by ATR and p53 [39,40]. Finally, ATM and ATR control cell cycle progression via phosphorylation of CHK1 and CHK2 [41][42][43].…”