クロモトリプシスはがんにおける遺伝子増幅の進化を促す
Ofer Shoshani1,2, Simon F Brunner3, Rona Yaeger4
1Ludwig Cancer Research, University of California at San Diego, La Jolla, CA, USA.
Nature
|December 28, 2020
まとめ
染色体トリプシスは癌細胞の染色体外DNA (ecDNA) の増幅を促し,薬剤耐性を促進する. このプロセスには DNA修復経路が関与し 癌治療の迅速な適応につながります
科学分野:
- ゲノミクス
- 癌 生物学
- 分子腫瘍学
背景:
- 焦点染色体増幅は腫瘍遺伝子の過剰発現とがん治療への抵抗を誘発する.
- エクストラクロモソームDNA (ecDNA) 増幅は,がんの発生と薬剤耐性における重要なメカニズムである.
研究 の 目的:
- エクDNA増幅を駆動するメカニズムと,得られた化学抵抗におけるその役割を調査する.
- エクDNAの形成と進化におけるクロモトリプシスの役割を明らかにする.
主な方法:
- 薬剤耐性細胞の全ゲノム配列解析
- エクDNAの進化の縦断分析
- ECDNAと染色体の相互作用を研究するために,in situ Hi-C 配列化を行う.
- ヒトがんにおけるゲノム再配置プロフィールの分析
主要な成果:
- クロモトリプシスは,PARPとDNA- PKsに依存する,ecDNA増幅の主要な原動力である.
- クロモトリプシスによるecDNAの構造的進化は,薬物耐性をさらに高めます.
- ecDNAは染色体端の近くで結合し,DNA損傷時に再統合する.
- 染色体内増幅は,破裂-融合-ブリッジサイクルと,その後の破裂を経て,ecDNAに進化する.
結論:
- クロモトリプシスは,迅速なecDNA増幅とがんにおける薬剤耐性の獲得の主なメカニズムです.
- この発見は,クロモトリプシス,ecDNA,がん治療に対する耐性との関連を示しています.
- 同様のゲノムプロファイルは,薬剤耐性を持つヒトの癌で観察されています.
関連する概念動画
02:21Cancers Originate from Somatic Mutations in a Single Cell
13.6K
Cancer arises from mutations in the critical genes that allow healthy cells to escape cell cycle regulation and acquire the ability to proliferate indefinitely. Though originating from a single mutation event in one of the originator cells, cancer progresses when the mutant cell lines continue to gain more and more mutations, and finally, become malignant. For example, chronic myelogenous leukemia (CML) develops initially as a non-lethal increase in white blood cells, which progressively...
13.6K
02:37Gene Duplication and Divergence
7.5K
The seminal work of Ohno in 1970 popularized the idea of gene duplication and divergence. DNA sequence comparison studies reveal that a large portion of the genes in bacteria, archaebacteria, and eukaryotes was generated by gene duplication and divergence, indicating its critical role in evolution.
The duplicated copies of the gene are called Paralogs. Paralogs with similar sequences and functions form a gene family. Across several species, a large number of gene families are...
The duplicated copies of the gene are called Paralogs. Paralogs with similar sequences and functions form a gene family. Across several species, a large number of gene families are...
7.5K
02:53Adaptive Mechanisms in Cancer Cells
6.2K
Cancer cells accumulate genetic changes at an abnormally rapid rate due to the defects in the DNA repair mechanisms. From an evolutionary perspective, such genetic instability is advantageous for cancer development. Mutant cell lines accumulate a series of beneficial mutations that contribute to their progression into cancer.
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
6.2K
01:37Epigenetic Regulation
3.5K
Epigenetic changes alter the physical structure of the DNA without changing the genetic sequence and often regulate whether genes are turned on or off. This regulation ensures that each cell produces only proteins necessary for its function. For example, proteins that promote bone growth are not produced in muscle cells. Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
X-chromosome...
X-chromosome...
3.5K
01:46Epigenetic Regulation
32.5K
Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
32.5K
01:33Cancer-Critical Genes I: Proto-oncogenes
9.9K
Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
9.9K