G-四重复稳定诱导B淋巴细胞中周心重复DNA序列的DNA断裂
Irina Waisertreiger1, Kalkidan Ayele1, Mehad Hilal Elshaikh1
1Department of Microbiology and Molecular Genetics, University of California Davis, Davis, CA 95616.
概括
DNA G-四重复结构可能导致复制压力和基因组不稳定. 通过选择性向癌细胞,诱导DNA损伤和抑制增殖,G4稳定剂药物显示治疗潜力.
科学领域:
- 分子生物学
- 遗传学
- 癌症研究
背景情况:
- DNA二次G-四重复 (G4) 结构可以阻碍DNA复制.
- 由于G4处理缺陷的复制压力与B细胞癌和前恶性细胞有关.
- 基因组不稳定和染色体重组是癌症的标志,尤其是B细胞恶性瘤.
研究的目的:
- 研究G4稳定对原发性和恶性B细胞基因组不稳定的影响.
- 评估初级B细胞与恶性B细胞对G4稳定性的差异反应.
主要方法:
- 用PDS治疗小鼠初级B细胞和CH12淋巴瘤细胞.
- 在治疗细胞中分析DNA损伤,染色体断裂和重新排列.
- 细胞循环进展 (G2/M停止) 和化变化 (四化) 的评估.
主要成果:
- 在初级B细胞和恶性B细胞中诱导了核糖体DNA和周心细胞区域的DNA断裂和重新排列.
- 在PDS治疗后,初级B细胞呈现出高水平的四形形细胞和二心染色体.
- 恶性CH12细胞激活了G2/M检查点,防止了四平体和主要细胞的广泛损伤.
结论:
- 主要和恶性B细胞对G4稳定化合物的反应不同.
- 皮里多斯塔丁导致显著的基因组不稳定性,恶性B细胞表现出更强大的检查点介导抗性.
- 通过利用差异细胞反应,G4稳定药物对选择性向B细胞瘤生长具有治疗意义.
相关概念视频
Fixing Double-strand Breaks
12.9K
The double-stranded structure of DNA has two major advantages. First, it serves as a safe repository of genetic information where one strand serves as the back-up in case the other strand is damaged. Second, the double-helical structure can be wrapped around proteins called histones to form nucleosomes, which can then be tightly wound to form chromosomes. This way, DNA chains up to 2 inches long can be contained within microscopic structures in a cell. A double-stranded break not only damages...
12.9K
Homologous Recombination
51.7K
The basic reaction of homologous recombination (HR) involves two chromatids that contain DNA sequences sharing a significant stretch of identity. One of these sequences uses a strand from another as a template to synthesize DNA in an enzyme-catalyzed reaction. The final product is a novel amalgamation of the two substrates. To ensure an accurate recombination of sequences, HR is restricted to the S and G2 phases of the cell cycle. At these stages, the DNA has been replicated already and the...
51.7K
Translesion DNA Polymerases
10.1K
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...
10.1K
Long-patch Base Excision Repair
7.2K
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:
7.2K
Restarting Stalled Replication Forks
5.9K
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,...
5.9K
Single-Strand DNA Binding Proteins
14.9K
For successful DNA replication, the unwinding of double-stranded DNA must be accompanied by stabilization and protection of the separated single strands of the DNA. This crucial task is performed by single-strand DNA-binding (SSB) proteins. They bind to the DNA in a sequence-independent manner, which means that the nitrogenous bases of the DNA need not be present in a specific order for binding of SSB proteins to it. The binding of SSB proteins straightens single-stranded DNA (ssDNA) and makes...
14.9K


