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Review
. 2022 Aug 31;50(4):1105-1118.
doi: 10.1042/BST20220049.

Processing DNA lesions during mitosis to prevent genomic instability

Anastasia Audrey #  1 , Lauren de Haan #  1 , Marcel A T M van Vugt  1 , H Rudolf de Boer  1
Affiliations
Review

Processing DNA lesions during mitosis to prevent genomic instability

Anastasia Audrey et al. Biochem Soc Trans. .

Abstract

Failure of cells to process toxic double-strand breaks (DSBs) constitutes a major intrinsic source of genome instability, a hallmark of cancer. In contrast with interphase of the cell cycle, canonical repair pathways in response to DSBs are inactivated in mitosis. Although cell cycle checkpoints prevent transmission of DNA lesions into mitosis under physiological condition, cancer cells frequently display mitotic DNA lesions. In this review, we aim to provide an overview of how mitotic cells process lesions that escape checkpoint surveillance. We outline mechanisms that regulate the mitotic DNA damage response and the different types of lesions that are carried over to mitosis, with a focus on joint DNA molecules arising from under-replication and persistent recombination intermediates, as well as DNA catenanes. Additionally, we discuss the processing pathways that resolve each of these lesions in mitosis. Finally, we address the acute and long-term consequences of unresolved mitotic lesions on cellular fate and genome stability.

Keywords: DNA damage response; cell cycle; genome instability; genome integrity; mitosis.

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Conflict of interest statement

The authors declare that there are no competing interests associated with the manuscript.

Figures

Figure 1.
Figure 1.. Regulation of DNA damage response throughout the cell cycle.
(A) Cells are equipped with checkpoints that regulate cell cycle progression upon DNA damage. ATR and ATM are key upstream checkpoint kinases that co-ordinate the DDR in response to single-strand DNA (ssDNA) and double-strand breaks (DSBs), respectively. Whereas ATM can be activated throughout interphase (orange line), ATR activation is restricted to S/G2 phase (brown line). Contrary to interphase, DNA damage does not halt cell cycle progression in mitosis. (B) In response to DSBs, cells utilize two canonical pathways to repair DSBs. Whereas canonical non-homologous end joining (c-NHEJ) is active throughout interphase, homologous recombination (HR) allows for templated repair sister chromatids become present in S/G2 phase. When these canonical pathways are not active due to genetic or experimental perturbations, alternative repair pathways, including break-induced replication (BIR), single-strand annealing (SSA), and alternative end joining (Alt-EJ), will be employed. The absence of canonical repair pathways is reminiscent of the mitotic state, in which mitotic kinases CDK1 and PLK1 inactivate many HR and c-NHEJ factors through phosphorylation.
Figure 2.
Figure 2.. Processing of DNA lesions in mitosis.
DNA lesions that end up in mitosis are processed by distinct pathways. (Left) Under-replicated DNA originating from perturbed replication in S-phase are subjected to DNA synthesis in early mitosis (MiDAS), involving TRAIP-mediated disassembly of the replisome complex, cleavage of the stalled replication fork by the MUS81 endonuclease, RAD52-mediated homology search and POLD3-dependent DNA synthesis. (Center) Unresolved homologous recombination (HR) intermediates are processed by structure-specific nucleases upon mitotic entry. Dissolution via the BTR (BLM, TOP3A, RMI1/2) complex results in a non-crossover repair product, whereas resolution either via GEN1 or the MUS81–EME1–SLX1–SLX4 complex gives rise to a repair product with the possibility of crossover. Dotted lines indicate possible cleavage patterns by structure-specific nucleases. (Right) Intertwined DNA molecules in the form of catenanes are resolved by topoisomerase IIα (TOP2A) during the metaphase–anaphase transition.
Figure 3.
Figure 3.. Unresolved lesions in mitosis are processed into ultrafine DNA bridges.
Failure to process joint DNA molecules in mitosis leads to persistent entangling of sister chromatids, generating ultrafine DNA bridges (UFBs) as cells progress into anaphase. Pulling force from mitotic spindle stretches the DNA, initiating binding of the PICH translocase to double-stranded DNA (dsDNA) regions of the UFB, and subsequent recruitment of the BTR (BLM, TOP3A, RMI1/2) complex and RIF1. RIF1 may interact with its effector protein phosphatase 1 (PP1), dephosphorylating PICH and BLM. The BLM helicase becomes activated and unwinds dsDNA into ssDNA, triggering localization of the RPA trimeric complex. Topoisomerase TOP3A may in turn decatenate ssDNA stretches to mediate resolution of UFBs. ‘C-UFB’ = centromeric UFB, ‘HR-UFB’ = homologous recombination UFB, ‘FS-UFB’ = fragile site UFB.
Figure 4.
Figure 4.. Tethering of DSB ends in mitosis.
(Top right) DSBs arising in mitosis can originate from ionizing radiation, experimental approaches using nuclease-mediated cleavage, as well as from mitotic processing of DNA lesions. (Zoom in, bottom left) At the damage site, recruitment of MDC1 mediates accumulation of TOPBP1 and CIP2A complexes, resulting in the tethering of two broken DNA ends in mitosis. TOPBP1 and CIP2A possibly form tethering complexes through interaction between its own homodimers and/or each other. Nucleases, including MRE11, may perform resection of broken DNA ends, allowing the loading of RPA onto ssDNA stretches, subsequently protecting them from nucleolytic degradation. Altogether, assembly of these factors forms a tethering structure that prevents the mis-segregation of broken, acentric, chromosomal arms, and formation of micronuclei. (Bottom right) DSB ends may remain tethered until cells progress to the next cell cycle in which canonical repair pathways are active. Alternatively, tethering may be an intermediate step prior to further processing by non-canonical repair factors activated in mitosis.
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