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Anaphase Bridges: Not All Natural Fibers Are Healthy G C A T T A C G G C A T genes Review Anaphase Bridges: Not All Natural Fibers Are Healthy Alice Finardi 1, Lucia F. Massari 2 and Rosella Visintin 1,* 1 Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20139 Milan, Italy; alice.fi[email protected] 2 The Wellcome Centre for Cell Biology, Institute of Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3BF, UK; [email protected] * Correspondence: [email protected]; Tel.: +39-02-5748-9859; Fax: +39-02-9437-5991 Received: 14 July 2020; Accepted: 5 August 2020; Published: 7 August 2020 Abstract: At each round of cell division, the DNA must be correctly duplicated and distributed between the two daughter cells to maintain genome identity. In order to achieve proper chromosome replication and segregation, sister chromatids must be recognized as such and kept together until their separation. This process of cohesion is mainly achieved through proteinaceous linkages of cohesin complexes, which are loaded on the sister chromatids as they are generated during S phase. Cohesion between sister chromatids must be fully removed at anaphase to allow chromosome segregation. Other (non-proteinaceous) sources of cohesion between sister chromatids consist of DNA linkages or sister chromatid intertwines. DNA linkages are a natural consequence of DNA replication, but must be timely resolved before chromosome segregation to avoid the arising of DNA lesions and genome instability, a hallmark of cancer development. As complete resolution of sister chromatid intertwines only occurs during chromosome segregation, it is not clear whether DNA linkages that persist in mitosis are simply an unwanted leftover or whether they have a functional role. In this review, we provide an overview of DNA linkages between sister chromatids, from their origin to their resolution, and we discuss the consequences of a failure in their detection and processing and speculate on their potential role. Keywords: SCI; anaphase bridges; topoisomerases; catenane 1. Sister Chromatid Intertwines: Structure, Origin and Resolution Sister chromatid intertwines (SCIs) represent an additional source of cohesion between the chromatids. They arise during DNA replication and must be removed before cell division to preserve genome integrity. SCIs are usually classified based on their molecular structure, which reflects their origin. Three types of intertwines are recognized, namely short regions of un-replicated DNA, recombination intermediates and DNA catenanes (Figure1A). Irrespectively of their nature and location in the genome, SCIs naturally arise during DNA replication and are mainly resolved in S phase, although some do persist and must be fully removed during mitosis to allow faithful chromosome segregation. Intertwines that persist through mitosis manifest themselves as DNA threads stretching between the two segregating DNA masses, known as anaphase bridges (Figure1). Genes 2020, 11, 902; doi:10.3390/genes11080902 www.mdpi.com/journal/genes Genes 2020, 11, 902 2 of 29 Genes 2019, 10, x FOR PEER REVIEW 2 of 29 Figure 1. Three types of sister chromatid intertwines (SCIs) are observed during mitosis. (A) Molecular structuresFigure 1. ofThree late replicationtypes of sister intermediates, chromatid joint intertwines molecules (SCIs) (here are exemplified observed by during a double mitosis. Holliday (A) junction)Molecular and structures catenanes of arelate shown. replication Genomic intermedia loci at whichtes, joint each molecules type of SCI (here were exemplified observed are by indicateda double inHolliday the schematic junction) chromosomes. and catenanes The are consequence shown. Genomic of persistent loci at SCIs whic inh mitosiseach type – a.k.a. of SCI anaphase were observed bridges –are is shownindicated in the in drawnthe schematic cell. (B, Cchromosomes.) Representative The images consequence of (B) a chromatin of persistent bridge SCIs and in (Cmitosis) an ultra-fine – a.k.a. bridgeanaphase are bridges shown in– is retinal shown pigment in the drawn epithelium cell. ( (RPE-1)B,C) Representative cells. DNA-intercalating images of (B dye) a chromatin Hoechst in bridge cyan, Plk1-interactingand (C) an ultra-fine checkpoint bridge are helicase shown (PICH) in retinal in magenta.pigment epithelium Courtesy images (RPE-1) by cells. Neal DNA-intercalating Umbreit (B) and Mitchelldye Hoechst Leibowitz in cyan, (C). Plk1-interacting checkpoint helicase (PICH) in magenta. Courtesy images by Neal Umbreit (B) and Mitchell Leibowitz (C). Although the number of anaphase bridges increases in the presence of stress, such as treatment with replicationAlthough inhibitors the number or impairment of anaphase of DNA bridges repair increase pathways,s in the DNA presence bridges of arestress, observed such as even treatment in the absencewith replication of stressors inhibitors and in untransformedor impairment cells,of DNA especially repair pathways, at the centromeres DNA bridges in mammalian are observed cells even [1,2]. Inin addition,the absence anaphase of stressors bridges and also in untransformed form when cells cells, attempt especially to segregate at the dicentriccentromeres chromosomes in mammalian that resultcells [1,2]. from telomere-to-telomereIn addition, anaphase fusion bridges [3–5]. also In contrast form towhen the othercells classesattempt of SCIs,to segregate which are dicentric thought tochromosomes occur during that normal result DNA from metabolism,telomere-to-telomere telomere fusion fusions [3–5]. are triggered In contrast by to telomere the other disfunction, classes of whichSCIs, which can be are caused thought by excessive to occur during telomere normal shortening DNA ormetabolism, by malfunctioning telomere of fusions the sheltering are triggered complex by thattelomere protects disfunction, chromosome which ends can (reviewed be caused in by Reference excessive [ 6telomere]). shortening or by malfunctioning of the shelteringAnaphase complex bridges canthat be protects classified chro asmosome either chromatin ends (reviewed bridges in or Reference ultra-fine bridges[6]). (UFBs), based on whetherAnaphase or not bridges the DNA can isbe chromatinized classified as (i.e.,either packaged chromatin with bridges histones or and ultra-fine other proteins) bridges and(UFBs), can bebased stained on whether with DNA or not dyes the like DNA Hoechst is chromatinized (Figure1B,C). (i.e., In unperturbedpackaged with conditions, histones and chromatin other proteins) bridges areand rare can and,be stained in yeast, with they DNA are dyes mostly like attributed Hoechst (F toigure unresolved 1B,C). In recombination unperturbed conditions, intermediates chromatin [7]. On thebridges other are hand, rare UFBsand, in can yeast, be observed they are inmostly the majority attributed of to cells unresolved in anaphase, recombination and they are intermediates enriched at the[7]. centromereOn the other in hand, human UFBs cells can [1,7 ].be The observed samekind in the of majority stressor canof cells often in induce anaphase, formation and they of both are typesenriched of bridges at the centromere (i.e., chromatinized in human and cells non-chromatinized), [1,7]. The same kind suggesting of stressor thatcan bothoften caninduce arise formation from the sameof both kind types of DNAof bridges intertwining. (i.e., chromatinized Currently, it and is not non-chromatinize clear what determinesd), suggesting the chromatinized that both can status arise of from the same kind of DNA intertwining. Currently, it is not clear what determines the chromatinized status of DNA bridges. Chromatin bridges may evolve into UFBs, according to the stage of their Genes 2020, 11, 902 3 of 29 DNA bridges. Chromatin bridges may evolve into UFBs, according to the stage of their resolution. Alternatively, the chromatinized status of a bridge may be determined at the time of its formation. In the latter case, DNA chromatinization may depend on several factors, such as the extent of intertwining or the timing of recognition during mitosis. Certain DNA intertwines are more commonly retained at specific loci. However, since different types of linkages can form anaphase bridges at the same region, their position in the genome is not sufficient to infer their molecular structure. 1.1. Incomplete Replication and Recombination Intermediates Un-replicated regions provide a source of DNA linkages called late-replication intermediates (LRIs). LRIs are bonds between the two—otherwise fully replicated—sister chromatids and consist of short un-replicated double-stranded DNA (dsDNA) segments, where the two parental strands still anneal to each other. Since replication is generally completed well before anaphase, LRIs usually do not evolve into anaphase bridges. Instead, anaphase bridges can form in conditions of replication stress, preferentially at late replicating or hard-to-replicate regions, like common fragile sites (CFSs) [2]. Indeed, in human cells, replication of fragile sites is often left incomplete, particularly under conditions of replicative stress, leading to DNA damage in the next cell cycle [8,9]. Another region that poses a challenge to replication is the telomere, as it contains repeated DNA sequences and tends to form G-quadruplexes, secondary DNA structures that can stall the replication fork. Consistently, telomeric anaphase bridges increase if replication of these regions is impaired, for example by depletion of the Werner helicase, which contributes to the resolution of G-quadruplexes
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