TY - JOUR

T1 - Chromothripsis and DNA Repair Disorders

AU - Nazaryan-Petersen, Lusine

AU - Bjerregaard, Victoria Alexandra

AU - Nielsen, Finn Cilius

AU - Tommerup, Niels

AU - Tuemer, Zeynep

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

KW - chromothripsis

KW - structural variants

KW - DNA repair

KW - DNA repair disorders

KW - DNA double-strand breaks (DSBs)

KW - ataxia telangiectasia mutated (ATM)

KW - ataxia telangiectasia and Rad3-related (ATR)

KW - TP53

KW - micronuclei

KW - chromosome pulverization

KW - BLOOM-SYNDROME PROTEIN

KW - CHROMOSOME SEGREGATION

KW - MITOTIC CATASTROPHE

KW - REARRANGEMENTS

KW - CANCER

KW - BREAKS

KW - INSTABILITY

KW - DAMAGE

KW - LOCALIZATION

KW - REPLICATION

U2 - 10.3390/jcm9030613

DO - 10.3390/jcm9030613

M3 - Review

C2 - 32106411

VL - 9

JO - Journal of Clinical Medicine

JF - Journal of Clinical Medicine

SN - 2077-0383

IS - 3

M1 - 613

ER -