Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
ReviewRole of specialized DNA polymerases in the limitation of replicative stress and DNA damage transmission
Introduction
The replication fork progression is constantly faced with different endogenous or exogenous impediments all along the genome. Exogenous barriers include DNA damage produced by genotoxic components from the environment, radiation, therapeutic treatments and the diet. In contrast, endogenous obstacles come from inherent DNA structures and composition, protein-DNA complexes, modification of the nucleotide pool, the production of oxidative species, transcription-replication machinery collisions, mutations in tumor suppressor genes and oncogenic protein expression [1]. These damaged or difficult-to-replicate DNA regions induce replication fork slowing or stalling, also known as “replicative stress” [2]. Replicative stress is mediated by the uncoupling of helicases from DNA replicative polymerases, generating long stretches of single-stranded DNA (ssDNA) [3]. This situation leads to S-phase checkpoint activation in order to organize replication fork restart but acute replicative stress can also induce collapsed forks and DNA breaks that need dedicated detection, signaling and appropriate DNA repair pathways [4].
Recently it was shown that mild replicative stress could escape checkpoint detection, leading to the persistence of under-replicated DNA regions or replication intermediates upon mitotic entry. Then, chromosome segregation induce breakage of these unresolved DNA regions that are transmitted to G1 daughter cells, detected by the formation of micronuclei and 53BP1 nuclear bodies [5]. DNA damage transmission caused by replicative stress has been clearly demonstrated at common fragile site loci (CFS) [6], [7]. In addition to CFS, it is possible that all genomic regions that are susceptible to be targeted by different sources of replication barriers or prone to form non-B DNA structures become a threat to accurate replication, promoting under-replicated DNA or replication intermediate transmission in mitosis and therefore the transmission of DNA damages to G1 daughter cells.
Genomic DNA synthesis during the replication process is mainly carried out by the B-family DNA polymerases δ, ε and α [8]. These replicative polymerases are also involved in other metabolic processes that need DNA synthesis, such as DNA repair and recombination [9]. In addition to these processive and accurate DNA polymerases, cells also use other polymerases to deal with the DNA replication under more particular situations, such as DNA distortions induced by DNA lesions and structured DNA sequences, or problematic cellular contexts leading to replicative stress. Specialized DNA polymerases are also more structurally adapted for the synthesis of challenging or precise and short DNA sequences. Indeed, they are monomeric (with the exception of Pol ζ), they can work without numerous accessory factors, they are exempted from exonuclease activity and their active polymerase site is more flexible [10]. The counterpart of these adaptive features is the poor fidelity of the specialized polymerases that requires restricted and tightly controlled activities [11], [12]. The specialized DNA polymerases are involved in genomic and cellular homeostasis and their functions in translesion synthesis (TLS) or in the DNA repair of exogenous damage are well established, however despite their error-prone reputation, more and more evidence is emerging to suggest that they also participate in the normal replication program [13], [14].
In this review, we highlight the functions of the specialized group of DNA polymerases that are described to work alongside or in concert with the replication machinery. We describe how they can avoid replication stress and DNA damage transmission thanks to their capacity to replicate non-B DNA structures and their role in rescuing stalled replication fork. We particularly focus on the specialized DNA polymerases that have already been characterized as participating in genomic stability maintenance in the absence of exogenous stress.
Section snippets
CFS instability: alteration of the DNA replication program at the heart of the process
In mammalian cells, fragile sites (FS) are the most sensitive parts of the genome that lead to chromosome instability following the alteration of DNA replication [15]. FS are distinguished as being rare or common [16]. Rare FS are inherited in a Mendelian way, most of them are expressed under low concentration of folate and their instability is associated with an expansion of trinucleotide repeats or AT-rich minisatellites. Rare FS are found in less than 5% of individuals, while common FS (CFS)
Activation of the S-phase checkpoint
If stalled replication forks do not signal properly or are not correctly supported, they become completely disorganized and weakened, leading to their collapse and DNA breakage. In order to avoid such deleterious consequences, cells do their best to deal with constant replication stress using several distinct specific mechanisms that can detect and manage replication problems. Cells have specific repair responses for each type of DNA damage, but the intra-S checkpoint is unique in being able to
Late DNA synthesis or “last chance DNA synthesis”
Under conditions of replicative stress, cells can reach mitosis with under-replicated DNA. Late DNA synthesis is therefore their “last chance” mechanism to complete the replication of these regions before cell division. Importantly, late DNA synthesis was shown to be required to avoid the potentially deleterious transmission of chromosomal aberrations to daughter cells [43].
Conclusion
Specialized DNA polymerases have largely been described in terms of their functions in TLS and DNA damage repair. In this review, we have summarized the roles of these enzymes in the replication of non-B DNA structures and in the restart of stalled forks. Further, we have highlighted the requirement of specialized DNA polymerases for the restriction of replication stress and DNA damage transmission (Table 1). It is important to note that the established functions of these polymerases in TLS and
Acknowledgments
We thank Marie-Jeanne Pillaire and Dana Hodroj for stimulating discussions and proofreading.
This study was supported by La Ligue Nationale contre le cancer, Equipe labellisée 2017 (le Laboratoire d’excellence Toulouse-Cancer), l’Institut National du Cancer-INCA_ 10493, l’Agence Nationale du Cancer-PCR 2016 and ITMO Cancer Aviesan within the framework of the Cancer Plan.
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These authors contributed equally to the review.