The centromere, the structure at the crossroads of chromosomes, is among the least explored regions of DNA.

The genetic material there is extremely concentrated, and the sequences highly repetitive.

Using a combination of proteomics and electron microscopy, a study carried out at the FIRC Institute of Molecular Oncology in Milan has revealed that the centromere is protected from genetic damages that may occur during the duplication of chromosomes.

"When we were able to observe the mechanism, after years of research, there has been a succession of ‘wow’s in the lab!’. The large amount of unexpected results allowed us to shed light on the region that can be called the ‘dark matter’ of the genome," said Vincenzo Costanzo, from FIRC Institute of Molecular Oncology in Milan, coordinator of the study.

"Half of chromosomal alterations linked to cancer start in the centromere, and our study helps to understand why."

The research, published in Nature Cell Biology, analyses and reconstructs the structure of this complex area of the chromosome.

Researchers found that the centromere concentrates most of the DNA repair factors in order to maintain its integrity.

This ‘shield’ allows the centromere the luxury of silencing the mechanism which monitors the natural obstacles that the centromeric DNA sequences form during replication.

This phenomenon allows the rapid duplication of the centromere, but on the other hand exposes the cells to the risks linked to a malfunctioning of DNA repair.

"The fact that the centromere does not see obstacles of replication but instead relies on DNA repair to remedy the situation was for us the most surprising aspect” says Costanzo.

"This mechanism, if on the one hand facilitates the replication of this complex region of chromosome, on the other exposes it to errors that can facilitate tumour formation”.

The mechanism has been identified through the use of mass spectrometry.

“We have succeeded” explains Angela Bachi, head of Functional Proteomics at IFOM  “not only in identifying but also in quantifying, for the first time, the protein factors that specifically bind centromeric DNA and provide its shield."

The researchers believe that this discovery could have important therapeutic implications.

"The majority of chemotherapeutics acts on the mechanisms of cell division and DNA replication" says  Costanzo.

"Our discovery helps us understand how these therapies work and what could be done to increase their effectiveness."

Source: Nature Cell Biology