Centromere Distribution Governs Genome Integrity and Stress Response

Just like you might use a belt to keep your clothes in place, the centromere holds a pair of chromatids together and attaches it to the mitotic spindle during cell division to ensure that each daughter cell ends up with the correct number of chromosomes. Each chromosome has only one centromere. Composed of tightly packaged, rapidly evolving satellite DNA with conserved functions, centromeres pose conundrums on several levels.

Since their discovery, scientists have noted that the arrangement of centromeres in the nucleus between cell divisions differs among species, cell-types, cell-cycle stage, and the cell’s state of specialization, but neither the underlying mechanism of their seemingly random nuclear distribution nor its biological significance was clear, until now.

In a new study titled, “Two-step regulation of centromere distribution by condensin II and the nuclear envelope proteins,” published in the journal Nature Plants on August 1, 2022, an international team led by scientists at the University of Tokyo, have uncovered evidence for a mechanism that controls how centromeres are scattered in the nucleus that suggests centromere distribution in the nucleus plays a vital role in maintaining genome integrity, particularly under duress.

Centromeres (magenta) in non-Rabl configuration (upper panel) and Rabl configurations (lower panel) [Sachihiro Matsunaga, The University of Tokyo].

Chromosomal centromeres attached to microtubules and pulled to opposite poles of the cell during mitosis are retained in the chromatin structure even when the cell is done dividing. If the positions of centromeres upon cell division do not change, they cluster on one side of the nucleus. This default mode of centromere distribution is called the Rabl configuration after the 19th century cytologist Carl Rabl who was the first to note the continuity of chromosomes throughout cell division. In the Rabl configuration, the free ends of the chromatids—another region of condensed chromatin called telomeres—are clustered at the opposite end of the nucleus, with respect to the centromeres.

On the other hand, in some species centromeres and telomeres are evenly distributed at the periphery of the nucleus. This is called the non-Rabl configuration and involves an active rearrangement of centromeres and telomeres during interphase—the period between mitosis.

“The biological function and molecular mechanism of the Rabl or non-Rabl configuration has been a mystery across the centuries,” said Sachihiro Matsunaga, PhD, a professor at the University of Tokyo’s Graduate School of Frontier Sciences and corresponding author of the paper. “We successfully revealed the molecular mechanism to construct the non-Rabl configuration.”

Using the plant Arabidopsis thalianaalso known as thale cress, as their model for non-Rabl configuration, and its mutant form with a Rabl configuration, the scientists found the protein complexes CII (condensin II) and LINC (linker of nucleoskeleton and cytoskeleton) work together to determine centromere distribution during cell division.

“The centromere distribution for non-Rabl configuration is regulated independently by the CII- LINC complex and a nuclear lamina protein known as CRWN (crowded nuclei),” Matsunaga said.

CII is abundant at centromeres. Together with LINC, CII plays 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. This constitutes the first step of the two-step mechanism. Once the cell has divided and entered interphase, CRWN proteins stabilize the positions of the scattered centromeres on the inner surface of the nuclear envelope, in the second step.

One might expect that the position of centromeres and telomeres could influence the organization of chromatin and thereby regulate gene expression. To test this hypothesis, the authors analyzed gene expression profiles in A. thaliana with non-Rabl configuration and its Rabl-structure mutant. To their surprise, they found little difference in gene expression, indicating the robustness of chromatin organization regardless of the type of centromere distribution.

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

“This suggests that precise control of centromere spatial arrangement is required for organ growth in response to DNA damage stress, and there is no difference in tolerance to DNA damage stress between organisms with the non-Rabl and Rabl,” said Matsunaga said. “This suggests that the appropriate spatial arrangement of DNA in the nucleus regardless of Rabl configuration is important for stress response.”

Future studies will be focused on identifying the energetic trigger for spatial arrangement of specific DNA regions and the mechanism that recognizes specific DNA. Identifying these mechanisms could help develop methods to manipulate the arrangement of nuclear DNA, which in turn could help develop stress-resistant organisms without altering nucleotide sequences.

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