Micronucleus is not a potent inducer of the cGAS/STING pathway.

Micronuclei (MN) have been associated with the innate immune response. The abrupt rupture of MN membranes results in the accumulation of cGAS, potentially activating STING and downstream interferon-responsive genes. However, direct evidence connecting MN and cGAS activation has been lacking.

Chromosome instability induced by a single defined sister chromatid fusion.

Chromosome fusion is a frequent intermediate in oncogenic chromosome rearrangements and has been proposed to cause multiple tumor-driving abnormalities. In conventional experimental systems, however, these abnormalities were often induced by randomly induced chromosome fusions involving multiple different chromosomes. It was therefore not well understood whether a single defined type of chromosome fusion, which is reminiscent of a sporadic fusion in tumor cells, has the potential to cause chromosome instabilities.

Replication stress induces mitotic death through parallel pathways regulated by WAPL and telomere deprotection.

Mitotic catastrophe is a broad descriptor encompassing unclear mechanisms of cell death. Here we investigate replication stress-driven mitotic catastrophe in human cells and identify that replication stress principally induces mitotic death signalled through two independent pathways. In p53-compromised cells we find that lethal replication stress confers WAPL-dependent centromere cohesion defects that maintain spindle assembly checkpoint-dependent mitotic arrest in the same cell cycle.

Telomere biology in aging and cancer: early history and perspectives.

The ends of eukaryotic linear chromosomes are protected from undesired enzymatic activities by a nucleoprotein complex called the telomere. Expanding evidence indicates that telomeres have central functions in human aging and tumorigenesis. While it is undoubtedly important to follow current advances in telomere biology, it is also fruitful to be well informed in seminal historical studies for a comprehensive understanding of telomere biology, and for the anticipation of future directions.

[Regulation of senescence by telomeres and telomerase].

Telomeres are vital for chromosome end protection against activation of DNA damage response. Telomere attrition leads to cell cycle arrest, which underlies cellular senescence and can restrict tissue replenishment. Although stem cells express telomerase reverse tran- scriptase, which elongates telomeric DNA, its activity is not enough to fully compensate for chronic telomere shortening.

Cell death during crisis is mediated by mitotic telomere deprotection.

Tumour formation is blocked by two barriers: replicative senescence and crisis. Senescence is triggered by short telomeres and is bypassed by disruption of tumour-suppressive pathways. After senescence bypass, cells undergo crisis, during which almost all of the cells in the population die.

The telomere deprotection response is functionally distinct from the genomic DNA damage response.

Loss of chromosome end protection through telomere erosion is a hallmark of aging and senescence. Here we developed an experimental system that mimics physiological telomere deprotection in human cells and discovered that the telomere deprotection response is functionally distinct from the genomic DNA damage response. We found that, unlike genomic breaks, deprotected telomeres that are recognized as DNA damage but remain in the fusion-resistant intermediate state activate differential ataxia telangiectasia mutated (ATM) signaling where CHK2 is not phosphorylated.

A telomere-dependent DNA damage checkpoint induced by prolonged mitotic arrest.

Telomere shortening and disruption of telomeric components are pathways that induce telomere deprotection. Here we describe another pathway, in which prolonged mitotic arrest induces damage signals at telomeres in human cells. Exposure to microtubule drugs, kinesin inhibitors, proteasome inhibitors or the disruption of proper chromosome cohesion resulted in the formation of damage foci at telomeres.

Regulation of DNA replication by chromatin structures: accessibility and recruitment.

The initiation of DNA replication and the elongation of DNA strands take place in chromatin, a huge compound DNA-protein complex. Although the factors involved in the process of DNA replication have been largely elucidated, the underlying mechanisms that determine their behavior in the context of chromatin have only recently begun to be understood. It has been known that transcription is tightly regulated by the state of chromatin compaction, which governs the accessibility of DNA to trans-acting factors.

The heterochromatin protein Swi6/HP1 activates replication origins at the pericentromeric region and silent mating-type locus.

Heterochromatin is a structurally compacted region of chromosomes in which transcription and recombination are inactivated. DNA replication is temporally regulated in heterochromatin, but the molecular mechanism for regulation has not been elucidated. Among heterochromatin loci in Schizosaccharomyces pombe, the pericentromeric region and the silent mating-type (mat) locus replicate in early S phase, whereas the sub-telomeric region does not, suggesting complex mechanisms for regulation of replication in heterochromatic regions.