在人类瘤中,DNA聚合酶 ε 和 δ 变体在聚氨酸通道中驱动突变发生
Daria Ostroverkhova1, Kathrin Tyryshkin1, Annette K Beach2
1Department of Pathology and Molecular Medicine, School of Medicine, Queen's University, Kingston, ON, Canada.
Cell reports
|January 14, 2024
概括
在DNA聚合酶 ε (POLE) 的变化导致超突变癌症. 这项研究揭示了与这些突变相关的特定DNA序列特征,有助于识别新的癌症驱动因素.
科学领域:
- 基因组学就是基因组学.
- 癌症生物学 癌症生物学
- 分子遗传学 分子遗传学
背景情况:
- 已知DNA聚合酶 ε (POLE) 的变化会导致超变异性癌症,其特征是特定的AGA>ATA转换.
- 在这些癌症中,除了简单的三核酸基因外,更广泛的基因组背景和突变特征在很大程度上仍未被探索.
研究的目的:
- 调查与POLE突变癌症中超变异相关的扩展DNA序列背景.
- 开发一种基于突变特征的预测模型,用于识别基于突变特征的新型POLE驱动器.
- 探索POLE和POLD1驱动癌症之间的共享突变特征.
主要方法:
- 来自524个子宫内膜和395个结直肠瘤的全外体测序数据分析.
- 开发和应用机器学习分类器来识别突变特征.
- 在酵母中进行功能性测试,以验证已识别的POLE驱动器变体.
主要成果:
- 波尔突变瘤在至少六个连续 purin 的序列内表现出明显的 G>T 转换特征,具有位置偏好.
- 一个机器学习分类器成功地识别了以前未知的POLE驱动器的瘤.
- 两种新型驱动因子,即POLE-E978G和POLE-S461L,在功能上得到了验证;E978G影响聚合酶域.
- 具有POLD1驱动器的瘤共享了POLE超变的已识别的扩展签名.
结论:
- 这项研究扩大了对癌症超级突变机制的理解.
- 聚氨酸通道具有独特的突变性质,可以影响癌症基因组的进化.
- 这些发现为识别癌症驱动因素和理解它们的突变特征提供了一种新的方法.
相关概念视频
Proofreading
6.3K
Synthesis of new DNA molecules is carried out by the enzyme DNA polymerase, which adds nucleotides on the daughter strand complementary to the template DNA strand. DNA polymerase has a higher affinity to add the correct base and ensures fidelity during DNA replication. Furthermore, it exhibits proofreading activity during replication, using an exonuclease domain that cuts off incorrect nucleotides from the nascent DNA strand.
Errors During Replication are Corrected by the DNA Polymerase...
Errors During Replication are Corrected by the DNA Polymerase...
6.3K
Translesion DNA Polymerases
10.0K
Translesion (TLS) polymerases rescue stalled DNA polymerases at sites of damaged bases by replacing the replicative polymerase and installing a nucleotide across the damaged site. Doing so, TLS allows additional time for the cell to repair the damage before resuming regular DNA replication.
TLS polymerases are found in all three domains of life - archaea, bacteria, and eukaryotes. Of the different classes of TLS polymerases, members of the Y family are fitted with specialized structures that...
TLS polymerases are found in all three domains of life - archaea, bacteria, and eukaryotes. Of the different classes of TLS polymerases, members of the Y family are fitted with specialized structures that...
10.0K
Nucleotide Excision Repair
3.5K
DNA Distortion and Damage
Cells are regularly exposed to mutagens—factors in the environment that can damage DNA and generate mutations. UV radiation is one of the most common mutagens and is estimated to introduce a significant number of changes in DNA. These include bends or kinks in the structure, which can block DNA replication or transcription. If these errors are not fixed, the damage can cause mutations, which in turn can result in cancer or disease depending on which sequences are...
Cells are regularly exposed to mutagens—factors in the environment that can damage DNA and generate mutations. UV radiation is one of the most common mutagens and is estimated to introduce a significant number of changes in DNA. These include bends or kinks in the structure, which can block DNA replication or transcription. If these errors are not fixed, the damage can cause mutations, which in turn can result in cancer or disease depending on which sequences are...
3.5K
Mismatch Repair
4.9K
Organisms are capable of detecting and fixing nucleotide mismatches that occur during DNA replication. This sophisticated process requires identifying the new strand and replacing the erroneous bases with correct nucleotides. Mismatch repair is coordinated by many proteins in both prokaryotes and eukaryotes.
The Mutator Protein Family Plays a Key Role in DNA Mismatch Repair
The human genome has more than 3 billion base pairs of DNA per cell. Prior to cell division, that vast amount of genetic...
The Mutator Protein Family Plays a Key Role in DNA Mismatch Repair
The human genome has more than 3 billion base pairs of DNA per cell. Prior to cell division, that vast amount of genetic...
4.9K
Genome 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
Overview of DNA Repair
31.0K
In order to be passed through generations, genomic DNA must be undamaged and error-free. However, every day, DNA in a cell undergoes several thousand to a million damaging events by natural causes and external factors. Ionizing radiation such as UV rays, free radicals produced during cellular respiration, and hydrolytic damage from metabolic reactions can alter the structure of DNA. Damages caused include single-base alteration, base dimerization, chain breaks, and cross-linkage.
Chemically...
Chemically...
31.0K


