DNA damage tolerance in stem cells, ageing, mutagenesis, disease and cancer therapy

Abstract

The DNA damage response network guards the stability of the genome from a plethora of exogenous and endogenous insults. An essential feature of the DNA damage response network is its capacity to tolerate DNA damage and structural impediments during DNA synthesis. This capacity, referred to as DNA damage tolerance (DDT), contributes to replication fork progression and stability in the presence of blocking structures or DNA lesions. Defective DDT can lead to a prolonged fork arrest and eventually cumulate in a fork collapse that involves the formation of DNA double strand breaks. Four principal modes of DDT have been distinguished: translesion synthesis, fork reversal, template switching and repriming. All DDT modes warrant continuation of replication through bypassing the fork stalling impediment or repriming downstream of the impediment in combination with filling of the single-stranded DNA gaps. In this way, DDT prevents secondary DNA damage and critically contributes to genome stability and cellular fitness. DDT plays a key role in mutagenesis, stem cell maintenance, ageing and the prevention of cancer. This review provides an overview of the role of DDT in these aspects.

PrimPol primase mediates replication traverse of DNA interstrand crosslinks

“…Re-priming of DNA synthesis downstream of lesions in the template is now recognized as a prominent mechanism of DNA damage tolerance (DDT), next to those involving translesive synthesis or the temporary invasion of the complementary strand (template switch). DDT pathways mediate the passage of replication forks through damaged DNA, avoiding interruptions in DNA synthesis that could increase genome instability and leaving the lesions to be repaired post-replicatively (reviewed by Branzei and Szakal, 2016;Muñoz and Méndez, 2017;Vaisman and Woodgate, 2017;Pilzecker et al, 2019).…”

Mutagenic replication: target for tumor therapy?

“…The ensuing replication stress triggers the DNA damage response that includes cell cycle arrest, senescence or apoptosis. 1 Although chemotherapeutic drugs are widely used to treat cancer, they not only kill proliferating cancer cells, but also proliferating normal cells. This provokes doselimiting side effects for the patients, including hair loss, gastrointestinal and hematopoietic attrition and, on the longer term, features of premature aging.…”

“…Translesion synthesis (TLS) is a dominant damage tolerance mechanism, employing specialized DNA polymerases that are able to replicate across damaged nucleotides, which mitigates replication stress and thereby precludes full deployment of the DNA damage response. 1 However, since TLS polymerases inherently act in an error-prone fashion while replicating damaged nucleotides, they not only provide tolerance of nucleotide lesions but also generate mutations that are associated with tumor initiation and progression. With this in mind, it has been hypothesized that the inhibition of mutagenic TLS might (i) increase the responses of cancer to genotoxic chemotherapeutics and (ii) reduce the mutagenicity and tumorigenicity of chemotherapy (see Fig.…”

“…To address the feasibility of such a novel approach in cancer chemotherapy, Wojtaszek et al 2 have performed a screen for small-molecule inhibitors of REV1, a protein that, in addition to performing TLS at abasic sites and nucleotide lesions at the minor groove of the helix, controls other TLS polymerases including TLS polymerase η and REV7, a subunit of TLS polymerase ζ. 1 Amongst the roughly 10,000 compounds analyzed, Wojtaszek et al identified a 1,4-dihydroquinolin-4-one derivative, JH-RE-06, that induces the dimerization of REV1 molecules at their C-terminal domains, in an asymmetric fashion. This hides the REV7-binding domain of REV1 and therefore abolishes REV1/REV3/REV7mediated highly mutagenic TLS while leaving TLS by less mutagenic polymerases intact.…”

“…[3][4][5][6] Furthermore, mutagenic TLS is essential for the maintenance of normal tissues 7,8 by providing tolerance not only of genotoxic drugs but also of endogenous nucleotide lesions or of difficult-toreplicate genomic sequences (such as centromeric DNA, fragile sites or G-quadruplex structures). 1 Finally, TLS plays an important role in the diversification of the immune system. 9 Thus, systemic exposure to REV1 inhibitors might enhance endogenous or chemotherapy-induced toxicity towards proliferating normal tissues.…”