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Review
. 2020 Nov:95:102947.
doi: 10.1016/j.dnarep.2020.102947. Epub 2020 Aug 16.

Mechanisms of direct replication restart at stressed replisomes

Brooke A Conti  1 , Agata Smogorzewska  2
Affiliations
Review

Mechanisms of direct replication restart at stressed replisomes

Brooke A Conti et al. DNA Repair (Amst). 2020 Nov.
No abstract available

Keywords: direct replication restart; fork reversal; re-priming; replication stress; template switching; translesion synthesis.

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Figures

Figure 1.
Figure 1.. Mechanisms of direct replication fork restart defined as restart without disassembly of the replisome or replication fork breakage.
A compromised replication fork can be passively rescued by an adjacent ongoing replication fork or newly activated ‘dormant’ origin (A) [27]. Direct restart includes AEP primase-dependent re-priming downstream of the lesion (B), lesion bypass with the use of translesion (TLS) polymerases (C), and lesion bypass via template switching (TS) (D) (reviewed in [–26]). Fork reversal generates a substrate, resembling a “chicken foot,” that allows for lesion bypass via TS and fork restoration (E) [120].
Figure 2.
Figure 2.. Mechanisms of replication fork restoration from a reversed fork.
To resume DNA replication, a reversed fork can be restored to allow for bypass of a lesion. (A) Fork remodeling proteins responsible for creation of a reversed fork, can also catalyze fork restoration in vitro. When the nascent leading-strand is longer than the nascent lagging-strand, SMARCAL1-dependent fork restoration is stimulated by RPA [131]. HLTF and ZRANB3 can only weakly catalyze this substrate, and while they can catalyze fork restoration when the nascent lagging-strand is longer than the nascent leading-strand, this reaction is inhibited by the presence of RPA [130, 131]. (B) The RECQ family helicases can also promote fork restoration [132]. RECQ1, which is inhibited by PARP1-dependent poly-ADP-ribosylation, has been shown to be active when the nascent lagging-strand is longer than the nascent leading-strand or both nascent strands are of equal length [132], but its activity has yet to be determined on substrates where the nascent leading-strand is longer than the nascent-lagging strand. RECQ1 also protects forks from nascent degradation by DNA2 [133]. WRN helicase function is epistatic with DNA2 nuclease to promote replication restart [133]. A reversed fork processed by WRN and DNA2 can be restored through branch migration or homology-directed restoration. BLM promotes fork restoration [–137], although the details of its involvement need to be furthered studied. (C) Homology-directed restoration of replication may rely on classical homologous recombination factors: BRCA2 and RAD51. BRCA2 functions to load RAD51 onto the ssDNA overhang and subsequently RAD51 mediates strand-invasion and D-loop formation [119]. Whether RAD52 plays a role in fork restoration at an intact stalled replication fork is unknown.
Figure 3.
Figure 3.. DNA replication restart pathway choice.
When a replication fork encounters replication stress, DNA synthesis can resume through several processes to preserve genome integrity. The manner with which DNA replication resumes may be dependent on the location of the lesion. (1) Re-priming, TLS or TS can bypass lesions on the leading-strand. (1A) The leading-strand can be re-primed with PRIMPOL, which is transcriptionally upregulated in response to replication stress, can be recruited to the replication fork through interaction with RPA, and is stimulated by binding partner, POLDIP2 [61]. PRIMPOL has been primarily implicated in response to UV [40], [41] and BPDE [53] while its role in response to HU is still unclear [41], [42]. (1B) PCNA mono-ubiquitination on K164 can direct leading-strand restart through the use of TLS polymerases to bypass the lesion [–88]. Thus far, only Pol η [66],[65], Rev1 [183] and Pol κ [67] have been implicated in acting directly at the replication fork in response to UV and HU. (1C) PCNA poly-ubiquitination on K164 [122] and PCNA SUMOylation [165] can direct leading-strand restart through fork reversal and TS. Fork reversal is a ubiquitous response to all types of replication-stress inducing agents. However, functional consequences of lack of this response has not been studied for many agents and for some, including MMC, fork reversal is not necessary for cellular survival [184] (2) Lesions on the lagging-strand are likely easily bypassed with DNA Polymerase α-primase-dependent re-priming as has been demonstrated in biochemical reconstitution experiments using yeast proteins [33].
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