在头部和部癌症中,DNA聚合酶β表达调节了聚ADP-ribose介导的复制检查点
Md Maruf Khan1, Wynand P Roos2, Charlotte R Pearson2
1Department of Pharmacology & Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA; Department of Pathology and Laboratory Medicine, Warren Alpert Medical School & Legorreta Cancer Center, Brown University, Providence, RI 02912, USA.
DNA repair
|June 5, 2025
概括
在头癌中,抑制PARG会触发细胞死亡,但Polβ过度表达会导致抵抗. 结合PARG和ATR/CHK1抑制剂可以克服这种抗性,提供一种新的HNSCC治疗策略.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 癌症治疗方法 癌症治疗方法
背景情况:
- 头部和部状细胞癌 (HNSCC) 由于当前疗法的有效性有限和严重副作用,因此存在重大治疗挑战.
- DNA聚合酶β (Polβ) 在DNA复制压力和细胞对DNA损伤的反应中起着关键作用.
- 聚ADP-核糖酶 (PARG) 调节聚ADP-核糖酶 (PAR) 水平,影响DNA损伤反应途径.
研究的目的:
- 研究Polβ在HNSCC对PARG抑制剂的反应中的作用.
- 探索克服HNSCC中PARG抑制剂的Polβ介导耐药性的治疗策略.
- 评估将PARG抑制剂与ATR/CHK1抑制剂结合使用的疗效.
主要方法:
- 评估了HNSCC细胞中对PARG抑制的细胞反应,这些细胞具有不同的Polβ水平.
- 研究了复制应激,细胞循环停止和亡诱导.
- 进行了体外实验,将PARG抑制剂与ATR/CHK1抑制剂结合起来.
主要成果:
- 在HNSCC细胞中PARG抑制诱导了复制应激和亡,但Polβ过度表达减轻了这种反应.
- 过度表达Polβ的HNSCC细胞表现出对PARG抑制剂治疗的抗性.
- PARG和ATR/CHK1抑制剂的联合治疗显示出协同效应,克服了Polβ介导的耐药性.
结论:
- 聚β水平极大地影响HNSCC对PARG抑制剂的敏感性.
- 通过PARG和ATR/CHK1抑制剂的联合治疗来准Polβ介导的耐药性是HNSCC的一个有前途的策略.
- 这种方法为改善HNSCC治疗结果提供了潜在的新治疗范式.
更多相关视频
06:44Assessment of Global DNA Double-Strand End Resection using BrdU-DNA Labeling coupled with Cell Cycle Discrimination Imaging
Published on: April 28, 2021
3.9K
08:53Strand-Specific Analysis of Proteins at Replicating DNA Strands by Enrichment and Sequencing of Protein-Associated Nascent DNA Method
Published on: May 2, 2025
298
相关概念视频
01:31Proofreading
6.2K
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...
6.2K
02:37DNA Damage can Stall the Cell Cycle
9.1K
In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
9.1K
01:02The DNA Replication Fork
35.7K
An organism’s genome needs to be duplicated in an efficient and error-free manner for its growth and survival. The replication fork is a Y-shaped active region where two strands of DNA are separated and replicated continuously. The coupling of DNA unzipping and complementary strand synthesis is a characteristic feature of a replication fork. Organisms with small circular DNA, such as E. coli, often have a single origin of replication; therefore, they have only two replication...
35.7K
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
02:10Translesion DNA Polymerases
9.9K
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...
9.9K
00:55DNA Helicases
21.3K
DNA unwinding helicase enzymes are a type of motor protein. Motor proteins can translocate along filaments or polymers using energy generated from ATP hydrolysis. Helicases are involved in all the important cellular processes where DNA unwinding is required, such as DNA replication, repair, recombination, and transcription. They are present in all living organisms, but vary in their structure, function, and mechanism of action. For example, in prokaryotes, DnaB helicase binds and translocates...
21.3K