Meiotic cell cycle progression requires adaptation to a constitutive DNA damage signal

Meiotic chromosome segregation relies on synapsis and crossover recombination between homologous chromosomes. These processes require multiple steps that are coordinated by the meiotic cell cycle and monitored by surveillance mechanisms. In the nematode Caenorhabditis elegans, CHK-2 kinase is activated at meiotic entry; its activity is essential for homologous synapsis and DSB formation. CHK-2 is normally inactivated at mid-prophase, but how this occurs has not been established. Defects in synapsis or establishment of crossover intermediates delay meiotic progression by prolonging the activity of CHK-2. We report that CHK-2 is necessary and sufficient to inhibit crossover designation. We further find that CHK-2 is inactivated at mid-prophase by a pathway that mediates DNA damage checkpoint adaptation in proliferating human cells: Polo-like kinases, particularly PLK-2, phosphorylate and inhibit CHK-2 in response to formation of crossover intermediates. These findings help to illuminate the mechanisms of crossover assurance and meiotic cell cycle control.

Persistent broken chromosome inheritance drives genome instability

Persistent DNA damage arising from unrepaired broken chromosomes or telomere loss can promote DNA damage checkpoint adaptation, and cell cycle progression, thereby increasing cell survival but also genome instability. However, the nature and extent of such instability is unclear. We show, using Schizosaccharomyces pombe, that inherited broken chromosomes, arising from failed homologous recombination repair, are subject to cycles of segregation, DNA replication and extensive end-processing, termed here SERPent cycles, by daughter cells, over multiple generations. Following Chk1 loss these post-adaptive cycles continue until extensive processing through inverted repeats promotes annealing, fold-back inversion and a spectrum of chromosomal rearrangements, typically isochromosomes, or chromosome loss, in the resultant population. These findings explain how persistent DNA damage drives widespread genome instability, with implications for punctuated evolution, genetic disease and tumorigenesis.One Sentence SummaryReplication and processing of inherited broken chromosomes drives chromosomal instability.

DNA Damage Stress: Cui Prodest?

DNA is an entity shielded by mechanisms that maintain genomic stability and are essential for living cells; however, DNA is constantly subject to assaults from the environment throughout the cellular life span, making the genome susceptible to mutation and irreparable damage. Cells are prepared to mend such events through cell death as an extrema ratio to solve those threats from a multicellular perspective. However, in cells under various stress conditions, checkpoint mechanisms are activated to allow cells to have enough time to repair the damaged DNA. In yeast, entry into the cell cycle when damage is not completely repaired represents an adaptive mechanism to cope with stressful conditions. In multicellular organisms, entry into cell cycle with damaged DNA is strictly forbidden. However, in cancer development, individual cells undergo checkpoint adaptation, in which most cells die, but some survive acquiring advantageous mutations and selfishly evolve a conflictual behavior. In this review, we focus on how, in cancer development, cells rely on checkpoint adaptation to escape DNA stress and ultimately to cell death.

Checkpoint adaptation in repair-deficient cells drives aneuploidy and resistance to genotoxic agents

Human cancers frequently harbour mutations in DNA repair genes, rendering the use of DNA damaging agents as an effective therapeutic intervention. As therapy-resistant cells often arise, it is important to better understand the molecular pathways that drive resistance in order to facilitate the eventual targeting of such processes. We employ repair-defective diploid yeast as a model to demonstrate that, in response to genotoxic challenges, nearly all cells eventually undergo checkpoint adaptation, resulting in the generation of aneuploid cells with whole chromosome losses that have acquired resistance to the initial genotoxic challenge. We demonstrate that adaptation inhibition, either pharmacologically, or genetically, drastically reduces the occurrence of resistant cells. Additionally, the aneuploid phenotypes of the resistant cells can be specifically targeted to induce cytotoxicity. We provide evidence that TORC1 inhibition with rapamycin, in combination with DNA damaging agents, can prevent both checkpoint adaptation and the continued growth of aneuploid resistant cells.