NATURE: Chromatin fragmentation helps tumor resistance

Gene amplification has been first found in cells that are resistant to methotrexate, a dhFR inhibitor that has been used to treat cancer for more than 50 years.
-amplified DNA can be found in small circulating DNA called double minutes (DMs), a subtype of extrachromosome DNA (ecDNA) that can also be found in the chromosomal hoyn chromosome (HSRs).
previous studies have shown that local chromosomal amplification contributes to cancer by mediating the overexpression of cancer genes, and accelerates the development of drug resistance in cancer treatment by increasing the expression of genes that affect the efficacy of anti-cancer drugs.
Recently, researchers published a paper in the journal Nature that sequenced chemotherapy-resistant cell clone isolates throughout the genome and found that chromosomal fragmentation is the main driver of the amplification of circulating chromosome DNA (ecDNA), a process that relies on the catalytic substases of poly (ADP-RNA) polymerases (PARPs) and DNA-dependent protein kinases (DNA-PKcs).
longitudinal analysis showed that the structural evolution of ecDNA further improved drug tolerance through several additional rounds of chromosomal fragmentation.
in sitnt Hi-C sequencing shows that ecDNAs are preferred near the end of chromosomes, where they are re-integrated when DNA is damaged.
Initial chromosomal amplification, formed under low-level drug selection, underwent a continuous break-fusion-bridge cycle, resulting in amplifications longer than 100 megabytes, which were trapped in a phase bridge and then broken, resulting in microkernels, whose encapsulations were the substrates of chromosome fragmentation.
researchers have found similar genome re-scheduling associated with local gene amplification in human cancers with access to drug resistance or cancer gene amplification.
, it is suggested that chromosomal fragmentation is the main mechanism for accelerating genome DNA rearfraction and amplification into ecDNA, and can quickly gain tolerance to changing growth conditions.
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