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.
Highlights
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 (Figure 1)
Different DNA repair pathways have evolved to defend mammalian cells from various types of DNA damage, such as pyrimidine dimers, A–G or T–C mismatches, and single-strand or double-strand breaks caused by endogenous and exogenous factors. These DNA lesions are recognized and corrected by specific DNA repair mechanisms, e.g., mismatch repair (MMR) corrects the base–base mismatches and insertion/deletion mispairings generated during DNA replication and recombination [35]; base-excision repair is responsible for repairing single-strand breaks (SSBs) [36]; and homologous recombination (HR) and NHEJ/MMEJ repair DSBs [37] (Figure 2)
Summary
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 (Figure 1). 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]. WWhheenn DDSSBBss aarree uunnrreeppaaiirreedd,, ee..gg..,, iinn HHRR--mmeeddiiaatteedd DDNNAA rreeppaaiirr ddiissoorrddeerrss aass ddeessccrriibbeedd iinn the text, tthhiiss lleeaaddss ttoo cceelllluullaarr ttrraannssffoorrmmaattiioonn,, sseenneesscceennccee,,aanndd//oorrcceelllddeeaatthh. Med. 2020, 9, 613 a gain of function mutated autosomal dominant CXCR4 chemokine receptor gene served as a rescue mechanism and healed the patient with an autoimmune disorder (warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome) [34]
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