Our genetic information is stored on chromosomal DNA, but in cancer cells, portions of chromosomes are excised and circularized, leading to accumulation of circular DNA. This circular DNA contains genes that promote cancer development and is involved in cancer onset and progression, as well as drug resistance where anticancer drug effectiveness declines. However, how circular DNA is generated remained unknown.
A research group led by Associate Professor Mariko Sasaki at the National Institute of Genetics and Professor Takehiko Kobayashi at the Institute for Quantitative Biosciences at the University of Tokyo focused on a protein complex called CAF-1 using budding yeast, a model eukaryotic organism that also represents human cells. CAF-1 assembles chromatin by depositing nucleosomes onto newly replicated DNA. The researchers showed that loss of CAF-1 leads to the production of circular DNAs derived from the ribosomal RNA gene region. They further found that this circular DNA is mistakenly formed during a repair process of DNA double-strand breaks that are formed when DNA replication stops.
Elucidating the mechanism by which CAF-1 suppresses circular DNA formation will contribute to understanding abnormal circular DNA formation in cancer cells in the future. Furthermore, the experimental system using budding yeast is expected to serve as a bridge from basic research to applied research and contribute to the development of drug discovery and medicine.
(Article: Masanori Nakajo)
(Right) When nucleosomes are not properly reconstructed after DNA replication, transcription that is normally repressed becomes active, and circular DNA is formed.