Chromothripsis and DNA Repair Disorders Nazaryan-Petersen, Lusine; Bjerregaard, Victoria Alexandra; Nielsen, Finn Cilius; Tommerup, Niels; Tuemer, Zeynep Published in: Journal of Clinical Medicine DOI: 10.3390/jcm9030613 Publication date: 2020 Document version Publisher's PDF, also known as Version of record Document license: CC BY Citation for published version (APA): Nazaryan-Petersen, L., Bjerregaard, V. A., Nielsen, F. C., Tommerup, N., & Tuemer, Z. (2020). Chromothripsis and DNA Repair Disorders. Journal of Clinical Medicine, 9(3), [613]. https://doi.org/10.3390/jcm9030613 Download date: 25. sep.. 2021 Journal of Clinical Medicine Review Chromothripsis and DNA Repair Disorders Lusine Nazaryan-Petersen 1,2, Victoria Alexandra Bjerregaard 3, Finn Cilius Nielsen 2, Niels Tommerup 1 and Zeynep Tümer 3,4,* 1 Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen, Denmark; [email protected] (L.N.-P.); [email protected] (N.T.) 2 Center for Genomic Medicine, Rigshospitalet, 2100 Copenhagen, Denmark; fi[email protected] 3 Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, 2600 Glostrup, Denmark; [email protected] 4 Department of Clinical Medicine, University of Copenhagen, 2200 Copenhagen, Denmark * Correspondence: [email protected]; Tel.: +45-292-048-55 Received: 28 January 2020; Accepted: 19 February 2020; Published: 25 February 2020 Abstract: Chromothripsis is a mutational mechanism leading to complex and relatively clustered chromosomal rearrangements, resulting in diverse phenotypic outcomes depending on the involved genomic landscapes. It may occur both in the germ and the somatic cells, resulting in congenital and developmental disorders and cancer, respectively. Asymptomatic individuals may be carriers of chromotriptic rearrangements and experience recurrent reproductive failures when two or more chromosomes are involved. Several mechanisms are postulated to underlie chromothripsis. The most attractive hypothesis involves chromosome pulverization in micronuclei, followed by the incorrect reassembly of fragments through DNA repair to explain the clustered nature of the observed complex rearrangements. Moreover, exogenous or endogenous DNA damage induction and dicentric bridge formation may be involved. Chromosome instability is commonly observed in the cells of patients with DNA repair disorders, such as ataxia telangiectasia, Nijmegen breakage syndrome, and Bloom syndrome. In addition, germline variations of TP53 have been associated with chromothripsis in sonic hedgehog medulloblastoma and acute myeloid leukemia. In the present review, we focus on the underlying mechanisms of chromothripsis and the involvement of defective DNA repair genes, resulting in chromosome instability and chromothripsis-like rearrangements. Keywords: chromothripsis; structural variants; DNA repair; DNA repair disorders; DNA double-strand breaks (DSBs); ataxia telangiectasia mutated (ATM); ataxia telangiectasia and Rad3-related (ATR); TP53; micronuclei; chromosome pulverization 1. Chromothripsis The mutational mechanism, termed chromothripsis, leading to complex genomic structural rearrangements in confined genomic regions, owes its identification to the development of genome-wide sequencing technologies [1]. Chromothripsis is characterized by local “shattering” or the generation of clustered DNA double-strand breaks (DSBs) involving one or multiple chromosomes and random reassembly of the generated fragments (Figure1). During the reassembly process, fragments may be deleted, while duplications are almost completely absent. Thus, chromothripsis is distinguished by (1) clustered breakpoints; (2) the oscillation of copy number states between one (deleted fragments with loss of heterozygosity) and two (with maintained heterozygosity); (3) rearrangements affecting a single haplotype (one of two homologous chromosomes); (4) the random order and orientation of the DNA fragments within the derivative chromosomes; and (5) the ability to “walk” through the derivative chromosome by joining the breakpoints if all the breakpoints are available [2]. J. Clin. Med. 2020, 9, 613; doi:10.3390/jcm9030613 www.mdpi.com/journal/jcm J. Clin. Med. 2020, 9, x FOR PEER REVIEW 2 of 9 toJ. Clin. “walk” Med. 2020through, 9, 613 the derivative chromosome by joining the breakpoints if all the breakpoints2 are of 9 available [2]. Figure 1. SchematicSchematic mechanism mechanism of of chromothripsis. The The first first step step of of chromothripsis is the generation of clustered clustered DNA DNA double-strand double-strand breaks. breaks. Chromothri Chromothripsispsis may may involve involve one one or ora few a few chromosomes, chromosomes, a chromosomala chromosomal arm arm (both (both p pand and q qarms), arms), or or an an entire entire chromosome. chromosome. This This results results in in multiple multiple fragments fragments thatthat are are stitched stitched together together in in a arandom random order order and and orientation orientation by byDNA DNA repair repair machineries. machineries. During During this process,this process, some some of the of thefragments fragments may may be belost. lost. Th Thee derivative derivative chromosome(s) chromosome(s) will will contain contain complex complex structuralstructural rearrangements. rearrangements. By By piecing piecing together together all all th thee structural structural variants variants detected detected by by paired-end paired-end or or mate-pair sequencing, it should be possible to delineate the derivative chromosomes. The detaileddetailed analysis analysis of the of breakpoint the breakpoint junction sequencesjunction showssequences few base-pair shows microhomologies,few base-pair microhomologies,if any, short deletions if /any,duplications, short deletions/dupl and short templatedications, or and nontemplated short templated insertions, or indicatingnontemplated that insertions,for most of indicating the cases, nonhomologousthat for most of end the joiningcases, (NHEJ)nonhomologous [3] and/or end microhomology-mediated joining (NHEJ) [3] and/or end microhomology-mediatedjoining (MMEJ) [4] are the mostend joining likely DNA (MMEJ) repair [4] mechanisms are the most underlying likely DNA the gluingrepair processmechanisms of the underlyinggenerated fragmentsthe gluing (Figure process2). of However, the generated in rare cases,fragments homologous (Figure repeats2). However, such asin SINE rare (shortcases, homologousinterspersed nuclearrepeats elements)such as SINE or LINE (short (long interspers intersperseded nuclear nuclear elements) elements) or elements LINE (long may interspersed also mediate nuclearchromothripsis, elements) as theyelements contain may potential also L1mediate endonuclease chromothripsis, cleavage sites, as resultingthey contain in DSBs, potential and could L1 endonucleasealso subsequently cleavage mediate sites, DNA resulting repair in via DSBs, homologous and could recombination also subsequently (HR) mediate within theDNA regions repair [5 via]. homologous recombination (HR) within the regions [5]. J. Clin. Med. 2020, 9, 613 3 of 9 J. Clin. Med. 2020, 9, x FOR PEER REVIEW 3 of 9 Figure 2.2. Double-strand breaks (DSBs) andand repairrepair mechanisms.mechanisms. Genotoxic factors, such as ionizingionizing radiation, reactivereactive oxygenoxygen species,species, andand toxictoxic environmentalenvironmental chemicalschemicals leadlead toto DNADNA damage,damage, whichwhich is didifferentfferent fromfrom aa mutationmutation occurringoccurring during DNA replication. Of the different different types of DNA lesions, double-strand breakage is the mostmost deleteriousdeleterious formform ofof DNADNA damage.damage. DSBs are repaired throughthrough didifferentfferent DNADNA repair pathways.pathways. Two main forms of DSB repair are homologous recombination (HR), whichwhich is an error-free DNADNA repair,repair, andand nonhomologousnonhomologous endend joiningjoining (NHEJ),(NHEJ), which is an error-prone DNA repair. When DSBs are unrepaired, e.g., in HR-mediatedHR-mediated DNA repair disorders as described in thethe text,text, thisthis leadsleads toto cellularcellular transformation,transformation, senescence,senescence, andand/or/or cellcell death.death. 2. Chromothripsis and Micronucleus Model Several hallmarks observed in chromothripticchromothriptic chromosomes suggest that these complex rearrangements occuroccur within within a single a single or few or subsequent few subsequent cell cycle(s) cell rather cycle(s) than occurringrather than progressively occurring overprogressively multiple cellover divisions multiple [cell1]. Thedivisions cause [1]. of the The localized cause of DSBsthe localized within relatively DSBs within small relatively regions issmall yet unclear,regions andis yet several unclear, hypotheses and several including hypotheses ionizing including radiation ionizing [1,6], the radiation breakage–fusion–bridge [1,6], the breakage– cycle associatedfusion–bridge with cycle telomere associated attrition [with1,7], abortedtelomere apoptosis attrition [8 ],[1,7], as well aborted as endogenous apoptosis endonucleases [8], as well [as5] haveendogenous been proposed endonucleases to play [5] a role. have The been most proposed favored to hypothesisplay a role. isThe the most formation favored of hypothesis a micronucleus, is the anformation extranuclear of a structuremicronucleus, with aan lipid extranuclear envelope, structure following with