Nazaryan-Petersen Lusine, Bjerregaard Victoria Alexandra, Nielsen Finn Cilius, Tommerup Niels, Tümer Zeynep
Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen, Denmark.
Center for Genomic Medicine, Rigshospitalet, 2100 Copenhagen, Denmark.
J Clin Med. 2020 Feb 25;9(3):613. doi: 10.3390/jcm9030613.
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 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.
染色体碎裂是一种导致复杂且相对聚集的染色体重排的突变机制，根据所涉及的基因组格局会产生多样的表型结果。它可发生于生殖细胞和体细胞中，分别导致先天性和发育性疾病以及癌症。无症状个体可能是染色体碎裂重排的携带者，当涉及两条或更多条染色体时会经历反复的生殖失败。有几种机制被认为是染色体碎裂的基础。最具吸引力的假说是微核中的染色体粉碎，随后通过DNA修复对片段进行错误的重新组装，以解释所观察到的复杂重排的聚集性质。此外，可能涉及外源性或内源性DNA损伤诱导以及双着丝粒桥形成。在患有DNA修复障碍的患者细胞中，如共济失调毛细血管扩张症、尼曼匹克氏症和布卢姆综合征，通常会观察到染色体不稳定。此外，在 Sonic hedgehog 髓母细胞瘤和急性髓系白血病中，某些基因的种系变异与染色体碎裂有关。在本综述中，我们聚焦于染色体碎裂的潜在机制以及有缺陷的DNA修复基因的参与，这会导致染色体不稳定和类似染色体碎裂的重排。
