During the progression of cancer cells, the degree of genome instability increases leading to genome chaos in populations of malignant cells. While normally chaos is associated with er-godicity, i.e., the state when the time averages of relevant parameters is equal to their phase space averages, the situation with cancer propagation is more complex. Chromothripsis, a catastrophic massive genomic rearrangement, is observed in many types of cancer leading to increased mu-tation rates. We present an entropic model of genome chaos and ergodicity and experimental evidence that increasing the degree of chaos beyond the non-ergodic threshold may lead to the self-destruction of the tumor cells. We study time and population averages of chromothripsis frequency in cloned rhabdomyosarcoma from rat stem cells. Clones with frequency above 10% result in cell apoptosis possibly due to mutations in the BCL2 gene. Potentially this can be used for suppressing cancer cells by shifting them into a non-ergodic proliferation regime.

Aneuploidy should compromise cellular proliferation but paradoxically favours tumour progression and poor prognosis. Here, we consider this paradox in terms of our most recent observations of chemo/radio-resistant cells undergoing reversible polyploidy. The latter perform segregation of two parental groups of end-to-end linked dyads by pseudo-mitosis creating tetraploid cells through a dysfunctional spindle. This is followed by autokaryogamy and homologous pairing preceding a bi-looped endo-prophase. The associated RAD51 and DMC1/γ-H2AX double-strand break repair foci are tandemly situated on the AURKB/REC8/kinetochore doublets along replicated chromosome loops, indicative of recombination events. MOS-associated REC8-positive peri-nucleolar centromere cluster organises a monopolar spindle. The process is completed by reduction divisions (bi-polar or with radial cytotomy including pedogamic exchanges) and release of secondary cells and/or formation of an embryoid. Together this process preserves genomic integrity and chromosome pairing, while tolerating aneuploidy by by-passing the mitotic spindle and meiotic SC checkpoints. Concurrently, it reduces the chromosome number and facilitates recombination that decreases the mutation load of aneuploidy and lethality in the chemo-resistant tumour cells. This cancer life-cycle has parallels both within the cycling polyploidy of the asexual life cycles of ancient unicellular protists and cleavage embryos of early multicellulars, supporting the atavistic theory of cancer.

Telomeres in epithelial tumours are usually maintained by telomerase, however, in the breast cancer MDA-MB-231 cell line, polyploid cells, induced by doxorubicin (DOX) were found, after mitotic slippage, transiently shifting to recombinatory alternative telomere lengthening (ALT) in PML bodies (APBs). The involvement of the meiotic recombination proteins was evidenced here by juxta-co-localisation of SPO11, DMC1 and RAD51/γH2AX with APBs in these and melanoma SkMel28-DOX-treated cells. Using sublethal doses of DOX we also observed the formation of the PML dimeric rod tandems linking γH2AX/TRF2 foci into ribbons discontinuously inserted into lamin B1 and circumventing cell nuclei. Next, we link these PML-lamin B1 insertions and peripheral rotation of the tandemly linked telomere repeats with the mobility of the nuclear envelope limited chromatin sheets (ELCS). ELCSs comprise two layers of the criss-crossed ~30 nm granules derived from surface heterochromatin (epichromatin) which contains telomere repeats enriched in GpC, PML, and ALU. ELCS protrude, circumvent, loop, split, fuse, and rejoin polyploid cell nuclei. We propose this gear-wheel-like turnover of telomere repeats to be used for the homology search. Interstitial and end-telomere repeats flanked by fragile ALU-Z flipons become recognised by SPO11 nuclease, attract TRF2, PML, and meiotic recombinases. Subsequently, they perform ALT recombining subtelomeres and telomeres or undergo non-homologous end-joining and chromosome rearrangements with ELCS. This mechanism increases the chance of cell survival and may be involved in chromothripsis.

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 underly chromothripsis. The most attractive hypothesis involves chromosome pulverization in micronuclei followed by 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.