Chromothripsis

Martin Poot, Poot, Martin

The highly complex structural genome variations chromothripsis, chromoanasynthesis, and chromoplexy are subsumed under the term chromoanagenesis, which means chromosome rebirth. Precipitated by numerous DNA double-strand breaks, they differ in number of and distances between breakpoints, associated copy number variations, order and orientation of segments, and flanking sequences at joining points. Results from patients with the autosomal dominant cancer susceptibility disorder Li-Fraumeni syndrome implicated somatic TP53 mutations in chromothripsis. TP53 participates in the G2/M phase checkpoint, halting cell cycling after premature chromosome compaction during the second half of the S phase, thus preventing chromosome shattering. By experimental TP53 ablation and micronucleus induction, one or a few isolated chromosomes underwent desynchronized replication and chromothripsis. Secondly, chromothripsis occurred after experimental induction of telomere crisis after which dicentric chromosomes sustained TREX1-mediated resolution of chromosome bridges and kataegis. Third, DNA polymerase Polθ-dependent chromothripsis has been documented. Finally, a family with chromothripsis after L1 element-dependent retrotransposition and Alu/Alu homologous recombination has been reported. Human chromosomal instability syndromes share defects in responses to DNA double-strand breaks, characteristic cell cycle perturbations, elevated rates of micronucleus formation, premature chromosome compaction, and apoptosis. They are also associated with elevated susceptibility to malignant disease, such as medulloblastomas and gliomas in ataxia-telangiectasia, leukemia and lymphoma in Bloom syndrome, and osteosarcoma and soft tissue sarcoma in Werner syndrome. The latter syndrome is characterized by a premature aging-like progressive decline of mesenchymal tissues. In all thus far studied cases, constitutional chromothripsis occurred in the male germline and male patients with defects in the double-strand break response genes ATM, MRE11, BLM, LIG4, WRN, and Ku70 show impaired fertility. Conceivably, chromothripsis may, in a stochastic rather than deterministic way, be implicated in germline structural variation, malignant disease, premature aging, genome mosaicism in somatic tissues, and male infertility.