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.

Bioinformatics and experimental findings reveal the therapeutic actions and targets of pachymic acid against cystitis glandularis

“…It is reported that TNF‐α is found in the promotion of cystitis in rat through inducing NF‐kappaB signaling pathway 30 . TP53, a tumor suppressor gene, is involved in cell cycle, senescence, and cell apoptosis via key gene regulation 31 . Since inflammation is strongly linked to canonical pathway, TP53 can inhibit inflammation in injured tissue 32 .…”

Extrachromosomal Circular DNA (eccDNA): From Chaos to Function

“…Several models of the eccDNA biogenesis have been proposed: 1) The chromothripsis model ( Figure 2A ): Chromothripsis is the catastrophic shattering of a chromosome followed by massive genomic rearrangement in a random order, leading to complex genomic structural rearrangements in confined genomic regions. As the “shattering” procedure results in clustered DNA double-strand breaks (DSBs), following by DNA repairing or aberrant DNA replication, and which make it a perfect circumstance to generate eccDNA ( Nazaryan-Petersen et al, 2020 ); in 2021, Wang’s team ( Wang Y et al, 2021 ) reported that apoptosis can promote eccDNA generation in human and mouse cells. It is not surprising; apoptosis, just like chromothripsis, can induce DNA fragmentation and may provide massive DNA fragments for eccDNA formation; 2) Episome model ( Figure 2B ).…”

Insight into the Molecular Basis Underlying Chromothripsis

“…The first written mention of the unambiguous detection of chromothripsis was published by Nazaryan et al in 2014. The paper emphasised the necessity of implementing several complementary methods (such as FISH, karyotyping and Sanger sequencing) in order to obtain the whole picture of complex rearrangements [ 64 , 65 ]. The topic of complex cth detection reappeared in 2016, when Macera et al published a report of chromothripsis diagnostics via multiple molecular biology approaches: karyotyping, fluorescence in situ hybridisation (FISH), microarray, whole genome sequencing approach.…”