New mutations by advanced entry of the genome into the replication phase lead to the origin of cancers as well as the development of its resistance to treatments, according to a new study by biologists from the University of Geneva (UNIGE), Switzerland. These genes induce cells to start replicating their DNA prematurely during the cell cycle and the abnormal cell division causes a tumor to develop. The results of the study are published in the journal Nature.
When a cell divides into two daughter cells, it must replicate its entire genome and transcribe part of it to make new proteins. Cell division is notably regulated by specific genes, including the proto-oncogenes Cyclin E and Myc. Their overexpression or mutation into oncogenes, following exposure of cells to a carcinogen for example, leads to uncontrolled proliferation of cells and promotes the formation of cancer. "We wanted to understand why numerous mutations accumulate in cells with activated oncogenes", explains Thanos Halazonetis, Professor at the Department of Molecular Biology of the UNIGE Faculty of Science.
Replication must begin between two genes
The UNIGE scientists have developed a method to identify the origins of replication on all chromosomes. This consists of isolating and sequencing the newly synthesized DNA from cells that have just entered the replication phase, in order to map on the genome the sites where replication has begun. This method, specifically developed for human cells, offers high degrees of sensitivity and resolution.
"Initially, the cell identifies all potential replication origins with a molecular marker. We have discovered that in normal cells, the aberrant replication origins are subsequently eliminated. This is the case for those that are located inside a gene, whereas they should be outside the genes so that the integral message of each gene is preserved", explains Morgane Macheret, a scientist at the Department of Molecular Biology at UNIGE and first author of the article.
When the cells skip steps
The activation of the oncogenes Cyclin E or Myc, on the other hand, induces the cells to begin replication of their DNA prematurely, without having had time to eliminate all the replication origins present in the genes. "The replication and transcription machineries are therefore active simultaneously on genes carrying a replication origin, which causes conflicts. Our analyses show that these conflicts induce DNA breakdowns, chromosomal rearrangements and, therefore, mutations", says Thanos Halazonetis.
Do these results explain the genomic instability present in different types of cancers? In order to answer this question, the biologists have studied an array of more than 500'000 chromosomal rearrangements already characterized in a wide range of tumors.
"We observed that these chromosomal defects are particularly common in the conflict zones we described. We hope that the discovery of the mechanism that partly or totally explains the genesis of this genomic instability will eventually lead to the development of new therapeutic strategies", concludes Morgane Macheret.