Health
Crushed chromosomes promote the growth of cancer cells
Researchers at the UC San Diego Branch of the University of California, San Diego School of Medicine and the Ludwig Cancer Institute have been published in the journal Nature and report on how the process of chromothripsis ultimately promotes cancer cell growth.
Chromothripsis is a mutational process in which up to thousands of clustered chromosomal rearrangements occur in a single event in a localized, limited genomic region on one or several chromosomes, cancer and congenital. It is known to be involved in both sexual disorders.
Chromothripsis means crushing chromosomes. Those that go through this process are first fragmented into many fragments and then restored in a random order by the DNA repair process. This is probably a non-homologous end bond.
“These relocations can occur in a single step.“Dr. Offer Shoshani, a postdoc in the lab of Dr. Don Cleveland, a professor of medicine, neuroscience, cell and molecular medicine at the University of California, San Diego School of Medicine, explained.
“During chromothripsis, intracellular chromosomes are shattered into many fragments, sometimes hundreds, and then reconstructed in a shuffled order. Some fragments are lost, but others. Fragments survive as extrachromosomal DNA (ecDNA). Some of these ecDNA elements promote the growth of cancer cells, forming fine-sized chromosomes called “double microchromosomes.”“
Earlier, the team discovered that up to half of all cancer cells in many types of cancer contain ecDNA, which carries genes that promote cancer. In this study, the team adopted direct visualization of chromosomal structures to identify the underlying mechanisms of gene amplification steps and resistance to methotrexate.
The entire genome of cell-developing drug resistance was sequenced, revealing that chromosomal disruption promotes the formation of ecDNA carrying genes that confer anticancer therapy resistance. In addition, the team observed how chromothripsis promotes ecDNA formation after intrachromosomal gene amplification.
“Chromothripsis converts intrachromosomal amplification (internal) to extrachromosomal (external) amplification, and the amplified ecDNA can be reintegrated into chromosomal positions in response to DNA damage from chemotherapy or radiation therapy.” Shoshani said. “A new study highlights the role of chromothripsis in all important stages of the DNA life cycle amplified in cancer cells and explains how cancer cells become more aggressive or drug resistant.”
“To prevent the development of drug resistance in cancer patients and improve results by repetitive DNA crushing as a driver of antineoplastic resistance and identifying DNA repair pathways required to reconstruct crushed chromosomal fragments. The rational design of combination drug therapy has become possible. “ Cleveland pointed out.
The findings suggest that chromothripsis is a major driver of accelerating genomic DNA rearrangement and amplification to ecDNA, enabling rapid acquisition of resistance to altered growth conditions.
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