The Centromere Distribution Guides Genome Integrity and Stress Response

The Centromere Distribution Guides Genome Integrity and Stress Response ...

The centromere secures a pair of chromatids together and secures it to the mitotic spindle during cell division to ensure that each daughter cell obtains the correct number of chromosomes. Centromeres pose problems on many levels.

Scientists have observed that the arrangement of centromeres in the nucleus between cell divisions varies between species, cell-types, cell-cycle stage, and the cells' state of specialization, but neither the primary mechanism of their seemingly random nuclear distribution nor its biological significance was clear until now.

An international team led by scientists at the University of Tokyo has discovered evidence for a mechanism that controls how centromeres are scattered in the nucleus, which may play a crucial role in maintaining genome integrity, particularly under pressure.

Centromeres in non-Rabl configurations (upper panel) and Rabl configurations (lower panel) [Sachihiro Matsunaga, The University of Tokyo]. If the free ends of the chromatids do not change, centromeres cluster on one side of the nucleus. In the Rabl configuration, the free ends of the chromatids have a similar structure to the centromeres.

Centromeres and telomeres are equally distributed at the periphery of the nucleus in some species, according to the non-Rabl configuration, which involves an active rearrangement of centromeres and telomeres during the interphase period between mitosis.

Sachihiro Matsunaga, PhD, a professor at the University of Tokyo's Graduate School of Frontier Sciences and corresponding author of the paper, has been a mystery over the centuries.

The researchers used Arabidopsis thaliana, also known as thale cress, as their model for a non-Rabl configuration, and its mutant form with a Rabl configuration. Both proteins, CII (condensin II) and LINC (linker of nucleoskeleton and cytoskeleton), cooperated to determine centromere distribution during cell division.

Matsunaga said the CII LINC complex and a nuclear lamina protein known as CRWN (crowded nuclei) regulate the centromere distribution in non-Rabl configuration independently.

CII is abundant at centromeres. Together with LINC, CII performs a role in scattering centromeres around the nuclear periphery during late anaphase, when the cell membrane invaginates, and telophase, when daughter cells physically separate during the terminal stages of cell division. In the second step, CRWN proteins stabilize the scattered centromeres on the inner surface of the nuclear envelope.

According to the authors, centromeres and telomeres might play a role in the organization of chromatin and thus regulate gene expression. A. thaliana with non-Rabl configuration and its Rabl-structure mutant found little difference in gene expression, demonstrating the robustness of chromatin organization regardless of the type of centromere distribution.

However, when the researchers applied DNA damage stress, they observed that the mutant with Rabl-structural configuration expanded organs at a slower rate than the normal plant.

Matsunaga said this suggests that precise control of centromere spatial arrangement is required for organ development in response to DNA damage stress. There is no difference in tolerance to DNA damage stress between organisms with the non-Rabl and Rabl configurations, thus the appropriate spatial arrangement of DNA in the nucleus is crucial for stress response.

Future research will focus on identifying the energetic trigger for spatial arrangement of specific DNA regions and the mechanism that recognizes specific DNA. These mechanisms might help develop techniques to manipulate nuclear DNA arrangement, which in turn might help develop stress-resistant organisms without altering nucleotide sequences.

You may also like: