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Deciphering centromeres to understand how cancer cells develop

03/03/2021

Centromeres are, in most of the cases in humans, the center of our chromosomes and play an essential role in the conservation of our genetic makeup during cell division. Changes to this process can cause cell transformation and, ultimately, can allow cancer to develop.

Manon Matias / Institut Curie

Researchers at Institut Curie, working alongside a Rockefeller University team, have shed light on the role of the protein CENP-A in favoring replication of centromeric DNA in order to avoid structural chromosomal abnormalities. The results of this research were published in the March 3rd 2021 issue of the PNAS Journal.
Over the course of human life, cells divide and reproduce to ensure the normal functioning of tissues and organs. This essential process must be functionally enabled in order to preserve the integrity of our genetic makeup. Firstly, DNA is duplicated in order to obtain two identical copies of each chromosome. This phenomenon is called DNA replication. These two copies are then distributed among the daughter cells during cell division.

Centromeres, which are the central region of chromosomes, ensure that DNA is appropriately distributed during cell division so that each new cell receives the same identical genetic heritage as its twin. Previous studies have already shown that centromeric dysfunction can cause chromosomes to be poorly distributed during cell division, leading to aneuploidy and possible cell transformation and cancer. In this new study, researchers from the Molecular Mechanisms of Chromosome Dynamics Team at Institut Curie, headed by Daniele Fachinetti, analyzed the fundamental mechanisms involved in the replication of centromeric DNA in order to accurately understand how it affects cancer cell formation.

Deciphering centromeres to understand how cancer cells develop

On the left, it is a montage of 3 different images that show human chromosomes visualized with a special probe mix named multicolor FISH. The centromeres aberrations are indicated by arrows together with the number of the chromosome involved. On the right, are the same chromosomes visualized with a centromeric DNA probes to show that the aberrations occurred at the level of the centromeric DNA. Also here the arrows marks the centromeres aberrations and the type of aberrations are spelled out.

Centromere: Fragile Sites of Study

90%

of cancers present aneuploidies

Cells with an incorrect number of chromosomes due to dysfunctional cell divisions, and structural chromosomal rearrangements (e.g. whole-arm translocations between them). Centromeres are often the site of such rearrangements, but the molecular mechanisms responsible for their appearance are not known. Certain chromosomal sites are known as “fragile,” because they are susceptible to gaps or breaks during DNA replication. These fragile sites are characterized by sequence repetitions (typically present at the centromeric regions) that can hinder replication and cause centromere breaks.

In this study, we show that a centromeric protein known as CENP-A protects intrinsically fragile human centromeres,

Explains Daniele Fachinetti, head of the Molecular Mechanisms of Chromosome Dynamics Lab at Institut Curie.

The absence of this protein causes breaks in centromeric DNA that lead to the formation of chromosomal rearrangements similar to those seen in cancer cells. We have established a clear connection between centromeric fragility and structural chromosome abnormalities.

He continues.

In the long term, this discovery may allow to use the centromere as a target of treatments designed to prevent the growth of cancer cells.

This research was funded by the French National Research Agency (ANR), by the Université PSL (Paris Sciences & Lettres) and the Association pour la Recherche sur le Cancer (ARC), that support the doctoral student who conducted it, Solène Hervé.

Centromeres: Why We Need Basic Research

Cell division is the process by which cells reproduce. It is essential for the growth, separation, and renewal of the various cells in our organism. At the end of the cell division process, each cell must carry 23 pairs of chromosomes that make up a functional human karyotype. When this process malfunctions, it produces dysfunctional cells that can lead to cancer or to developmental delays. It is thus clear that, in order to understand the mechanisms at work in these processes, we must first study them at the fundamental molecular level.

This is the focus of the Molecular Mechanisms of Chromosome Dynamics Team at Institut Curie: they study centromeres, the part of chromosomes that ensures their proper distribution throughout dividing cells. “For us, the most important thing to understand is what distinguishes a normal cell from an abnormal cell. We are trying to pinpoint all the mechanisms that can promote abnormal centromeres and cell division, which in turn produces cancerous cells,” explains lab director Daniele Fachinetti. “Our goal is to understand the role that centromeric instability plays in the increased incidence of cancer with age,” he adds.

Source: CENP-A chromatin prevents replication stress at centromeres to avoid structural aneuploidy, PNAS, xx xx 2021

Simona Giunta^1,†,*, Solène Hervé^2,†, Ryan R. White³, Therese Wilhelm², Marie Dumont², Andrea Scelfo², Riccardo Gamba², Cheng Kit Wong⁴, Giulia Rancati⁴, Agata Smogorzewska³, Hironori Funabiki^1,* & Daniele Fachinetti^2,*

† Equal contribution

*Corresponding authors

¹ The Rockefeller University, Laboratory of Chromosome and Cell Biology, 1230 York Ave,

New York, NY 10065 USA

² Institut Curie, PSL Research University, CNRS, UMR 144, 26 rue d’Ulm, F-75005, Paris,

France

³ The Rockefeller University, Laboratory of Genome Maintenance,1230 York Ave, New York,

NY 10065 USA

⁴ A*STAR Institute of Medical Biology, 8A Biomedical Grove, Immunos 138648, Singapore