在染色质上SIRT1的再分配促进了基因组的稳定性,但在衰老过程中改变了基因表达
Philipp Oberdoerffer1, Shaday Michan, Michael McVay
1Department of Pathology and Glenn Labs for Aging Research, Harvard Medical School, Boston, MA 02115, USA.
Cell
|December 2, 2008
概括
哺乳动物SIRT1,一个Sir2同类,通过抑制重复的DNA和基因来维护基因组稳定性. DNA损伤触发SIRT1转移到修复部位,减轻与年龄相关的基因表达变化并促进生存.
科学领域:
- 分子生物学分子生物学
- 遗传学 是一个遗传学.
- 衰老研究研究 衰老研究
背景情况:
- 基因组不稳定性和基因表达的改变是衰老的关键特征.
- 酵母Sir2沉默基因并稳定DNA,但在衰老过程中其转移会导致基因沉默和不育.
- Sir2的哺乳动物同类是SIRT1,这是一个参与各种细胞过程的蛋白质.
研究的目的:
- 研究哺乳动物SIRT1在维持基因组稳定性及其在衰老过程中的功能中的作用.
- 为了确定SIRT1在对DNA损伤的反应中表现的行为是否与酵母 Sir2的行为相似.
- 评估SIRT1表达增加对生存率和年龄相关的转录变化的影响.
主要方法:
- 利用小鼠胚胎干细胞研究SIRT1功能.
- 检查了SIRT1与重复性DNA和基因位置的相互作用.
- 研究SIRT1的局部化,以应对DNA损伤.
- 在基因组不稳定的小鼠模型中评估SIRT1表达增加的影响.
主要成果:
- 哺乳动物SIRT1抑制了重复的DNA和老鼠基因组中的多种基因组.
- 在DNA受损时,SIRT1与其目标位点分离,并迁移到DNA断裂,促进修复.
- 这种转移会导致类似于老老鼠大脑中观察到的转录变化.
- 增加SIRT1表达增加了基因组不稳定模型中的生存率,并抑制了与年龄相关的基因表达变化.
结论:
- SIRT1在抑制潜在有害的DNA元素和调节基因表达方面发挥着至关重要的作用.
- 由于DNA损伤引起的SIRT1再分配是一种保存机制,促进了基因组稳定性,并可能减缓衰老.
- 在DNA修复和基因调节中的SIRT1的功能突显了它在真核生物的衰老过程中的重要性.
更多相关视频
相关概念视频
02:31Replication in Eukaryotes
Overview
03:17Inheritance of Chromatin Structures
Epigenetics is the study of inherited changes in a cell's phenotype without changing the DNA sequences. It provides a form of memory for the differential gene expression pattern to maintain cell lineage, position-effect variegation, dosage compensation, and maintenance of chromatin structures such as telomeres and centromeres. For example, the structure and location of the centromere on chromosomes are epigenetically inherited. Its functionality is not dictated or ensured by the underlying DNA...
02:15Replicative Cell Senescence
Replicative cell senescence is a property of cells that allows them to divide a finite number of times throughout the organism's lifespan while preventing excessive proliferation. Replicative senescence is associated with the gradual loss of the telomere — short, repetitive DNA sequences found at the end of the chromosomes. Telomeres are bound by a group of proteins to form a protective cap on the ends of chromosomes. Embryonic stem cells express telomerase — an enzyme that adds the telomeric...
02:51mRNA Stability and Gene Expression
The structure and stability of mRNA molecules regulates gene expression, as mRNAs are a key step in the pathway from gene to protein. In eukaryotes, the half-life of mRNA varies from a few minutes up to several days. mRNA stability is essential in growth and development. The absence of the proteins regulating its stability, such as tristetraprolin in mice, can cause systemic issues, including bone marrow overgrowth, inflammation, and autoimmunity.
Cis-acting Elements involved in mRNA stability
Cis-acting Elements involved in mRNA stability
01:29Replication in Eukaryotes
In eukaryotic cells, DNA replication is highly conserved and tightly regulated. Multiple linear chromosomes must be duplicated with high fidelity before cell division, so there are many proteins that fulfill specialized roles in the replication process. Replication occurs in three phases: initiation, elongation, and termination, and ends with two complete sets of chromosomes in the nucleus.
Many Proteins Orchestrate Replication at the Origin
Eukaryotic replication follows many of the same...
Many Proteins Orchestrate Replication at the Origin
Eukaryotic replication follows many of the same...
02:15Replicative Cell Senescence
Replicative cell senescence is a property of cells that allows them to divide a finite number of times throughout the organism's lifespan while preventing excessive proliferation. Replicative senescence is associated with the gradual loss of the telomere — short, repetitive DNA sequences found at the end of the chromosomes. Telomeres are bound by a group of proteins to form a protective cap on the ends of chromosomes. Embryonic stem cells express telomerase — an enzyme that adds the telomeric...