C9orf72的扩张产生了不稳定的叶酸敏感脆弱部位FRA9A
bioRxiv : the preprint server for biology
|November 21, 2024
概括
C9orf72扩张导致FRA9A部位的叶酸敏感染色体脆弱,导致DNA损伤和ALS和FTD的免疫反应. 这种不稳定性是可转移的,并且与维生素缺乏有关.
科学领域:
- 遗传学 是一个遗传学.
- 分子生物学分子生物学
- 神经科学是一个神经科学.
背景情况:
- C9orf72 (GGGGCC) n扩展 (C9orf72 Exp) 与肌缩侧面硬化症 (ALS),前性痴呆症 (FTD) 和自身免疫性疾病有关.
- C9orf72 Exp患者表现出过度活跃的cGAS-STING免疫反应和DNA损伤,但这种DNA的来源尚不清楚.
- 含有C9orf72的Chr9p21位点不稳定,并与各种疾病有关.
研究的目的:
- 调查C9orf72 Exp中DNA损伤和免疫刺激的来源.
- 为了确定C9orf72 Exp是否导致染色体脆弱性.
主要方法:
- 用C9orf72 Exp对患者衍生细胞和大脑进行分析.
- 染色体脆弱性测定,包括姐妹染色体交换分析.
- 转基因C9orf72 Exp小鼠模型的生成和分析.
主要成果:
- C9orf72 Exp诱导了叶酸敏感的脆弱部位FRA9A,这是9p21的一个大型区域,包括C9orf72.
- 具有C9orf72 Exp的细胞表现出染色体不稳定性,包括重排和微核,提供内源性受损DNA.
- 在老鼠模型中,重复的不稳定性和脆弱性对叶酸敏感,并可转移到其他组织.
结论:
- C9orf72扩张引发了对维生素敏感的染色体脆弱性,在9p21位点产生了结构变异.
- 这种脆弱性有助于DNA受损的来源,在C9orf72相关疾病中驱动免疫反应.
- C9orf72重复的体质不稳定性和相关的染色体脆弱性是关键的致病机制.
相关概念视频
01:02Long-patch Base Excision Repair
7.0K
Since the discovery of the two BER pathways, there has been a debate about how a cell chooses one pathway over the other and the factors determining this selection. Numerous in vitro experiments have pointed out multiple determinants for the sub-pathway selection. These are:
7.0K
02:37Restarting Stalled Replication Forks
5.8K
DNA replication is initiated at sites containing predefined DNA sequences known as origins of replication. DNA is unwound at these sites by the minichromosome maintenance (MCM) helicase and other factors such as Cdc45 and the associated GINS complex.The unwound single strands are protected by replication protein A (RPA) until DNA polymerase starts synthesizing DNA at the 5’ end of the strand in the same direction as the replication fork. To prevent the replication fork from falling apart,...
5.8K
02:46Genome Copying Errors
4.2K
DNA replication is a well-evolved process that copies millions of base pairs with high fidelity during each cell division. Occasionally a wrong base or a long stretch of wrong bases may get added to the daughter strands. If the errors are left unchecked, cells might accumulate several mutations that might endanger their survival. Therefore, the copying errors are checked and repaired at three levels.
4.2K
02:27Nonsense-mediated mRNA Decay
10.6K
The Upf proteins that carry out nonsense-mediated decay (NMD) are found in all eukaryotic organisms, including humans. Each protein has an individual role, but they need to work in collaboration. Upf1 is an ATP-dependent RNA helicase that unwinds the RNA helix. Because Upf1 can unwind any RNA, Upf2 and Upf3 are required to help Upf1 discriminate between nonsense and normal mRNAs.
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...
10.6K
02:53Conservative Site-specific Recombination and Phase Variation
5.9K
Because the DNA segments are cut and reorganized in a direction-specific manner, site-specific recombination has emerged as an efficient genetic engineering technique. Flippase and Cyclization recombinases or Flp and Cre, respectively, are two members of the tyrosine recombinase family derived from bacteriophages, that are used to mediate site-specific DNA insertions, deletions, and targeted expression of proteins in mammalian cell lines.
The recognition sites for Cre recombinase called LoxP...
The recognition sites for Cre recombinase called LoxP...
5.9K
01:31Translation
14.6K
Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
Translation Produces the Building Blocks of Life
Proteins are...
Translation Produces the Building Blocks of Life
Proteins are...
14.6K