Interphase Chromosomes in Replicative Senescence: Chromosome Positioning as a Senescence Biomarker and the Lack of Nuclear Motor-Driven Chromosome Repositioning in Senescent Cells.

This study demonstrates, and confirms, that chromosome territory positioning is altered in primary senescent human dermal fibroblasts (HDFs). The chromosome territory positioning pattern is very similar to that found in HDFs made quiescent either by serum starvation or confluence; but not completely. A few chromosomes are found in different locations. One chromosome in particular stands out, chromosome 10, which is located in an intermediate location in young proliferating HDFs, but is found at the nuclear periphery in quiescent cells and in an opposing location of the nuclear interior in senescent HDFs. We have previously demonstrated that individual chromosome territories can be actively and rapidly relocated, with 15 min, after removal of serum from the culture media. These chromosome relocations require nuclear motor activity through the presence of nuclear myosin 1ß (NM1ß). We now also demonstrate rapid chromosome movement in HDFs after heat-shock at 42°C. Others have shown that heat shock genes are actively relocated using nuclear motor protein activity via actin or NM1ß (Khanna et al., 2014; Pradhan et al., 2020). However, this current study reveals, that in senescent HDFs, chromosomes can no longer be relocated to expected nuclear locations upon these two types of stimuli. This coincides with a entirely different organisation and distribution of NM1ß within senescent HDFs.

The genotoxicity of physiological concentrations of chromium (Cr(III) and Cr(VI)) and cobalt (Co(II)): an in vitro study.

Humans are exposed to chromium and cobalt in industry, from the environment and after joint replacement surgery from the CoCr alloy in the implant. In this study we have investigated whether Cr(III), Cr(VI), Co(II) and Cr in combination with Co could induce chromosome aberrations in human fibroblasts in vitro at the same concentrations that have been found in the peripheral blood of exposed humans. We used 24 colour M-FISH as a sensitive way to detect translocations and aneuploidy and examined the effects of a 24-h exposure and its consequences up to 30 days after the exposure in order to record genomic instability and/or repair. At these physiological doses the metals induced predominantly numerical rather than structural aberrations. Co was the least reactive and Cr(VI) especially in combination with Co the most. All metals at the highest physiological doses caused simple (gain or loss of 3 or less chromosomes) and complex (more than 49 chromosomes) aneuploidy. All metals at the lowest physiological dose caused a significant increase of total aberrations. Cr(VI) was much more effective than Cr(III) in causing chromosome fragments, which were only induced at the highest doses. There was a slow resolution of aneuploidy with time after exposure. This involved a reduction in the proportion of aneuploid cells and a reduction of the number of chromosomes within cells showing complex aneuploidy. We conclude that these metal ions can cause chromosome aberrations at physiological concentrations and that their main effect is aneugenic.

Alterations to nuclear architecture and genome behavior in senescent cells.

The organization of the genome within interphase nuclei, and how it interacts with nuclear structures is important for the regulation of nuclear functions. Many of the studies researching the importance of genome organization and nuclear structure are performed in young, proliferating, and often transformed cells. These studies do not reveal anything about the nucleus or genome in nonproliferating cells, which may be relevant for the regulation of both proliferation and replicative senescence. Here, we provide an overview of what is known about the genome and nuclear structure in senescent cells. We review the evidence that nuclear structures, such as the nuclear lamina, nucleoli, the nuclear matrix, nuclear bodies (such as promyelocytic leukemia bodies), and nuclear morphology all become altered within growth-arrested or senescent cells. Specific alterations to the genome in senescent cells, as compared to young proliferating cells, are described, including aneuploidy, chromatin modifications, chromosome positioning, relocation of heterochromatin, and changes to telomeres.