Chromothripsis and DNA Repair Disorders

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: DNA double-strand breaks (DSBs); DNA repair; DNA repair disorders; TP53; ataxia telangiectasia and Rad3-related (ATR); ataxia telangiectasia mutated (ATM); chromosome pulverization; chromothripsis; micronuclei; structural variants.

Figure 1

Schematic mechanism of chromothripsis. The first step of chromothripsis is the generation of clustered DNA double-strand breaks. Chromothripsis may involve one or a few chromosomes, a chromosomal arm (both p and q arms), or an entire chromosome. This results in multiple fragments that are stitched together in a random order and orientation by DNA repair machineries. During this process, some of the fragments may be lost. The derivative chromosome(s) will contain complex structural rearrangements. By piecing together all the structural variants detected by paired-end or mate-pair sequencing, it should be possible to delineate the derivative chromosomes.

Figure 2

Double-strand breaks (DSBs) and repair mechanisms. Genotoxic factors, such as ionizing radiation, reactive oxygen species, and toxic environmental chemicals lead to DNA damage, which is different from a mutation occurring during DNA replication. Of the different types of DNA lesions, double-strand breakage is the most deleterious form of DNA damage. DSBs are repaired through different DNA repair pathways. Two main forms of DSB repair are homologous recombination (HR), which is an error-free DNA repair, and nonhomologous end joining (NHEJ), which is an error-prone DNA repair. When DSBs are unrepaired, e.g., in HR-mediated DNA repair disorders as described in the text, this leads to cellular transformation, senescence, and/or cell death.

Figure 3

Micronucleus formation during mitotic cell division. A micronucleus can form when a chromosome lags in anaphase, resulting in missegregation and exclusion from the main nucleus upon cytokinesis. This can, for example, occur when the bipolar mitotic spindle fails to capture and segregate chromosomes because of microtubule/kinetochore malfunction (above) or when sister chromatids are entangled throughout mitosis by unresolved replication intermediates (arising in S-phase) that persist as DNA bridges (below) and prohibit faithful segregation. Chromosomes entrapped in micronuclei are accompanied by an unstable nuclear envelope and show delayed replication and susceptibility to DSBs and pulverization. These dramatic mitotic segregation errors are proposed to lead to the dramatic chromosomal rearrangements observed in chromothripsis.