在癌症中,APOBEC3A诱导的DNA损伤驱动了聚合酶 θ 依赖性和合成致命性
Abhishek Bose1, Weisi Liu1, Paul Yoo1
1Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
bioRxiv : the preprint server for biology
|November 24, 2025
概括
APOBEC3酶导致癌症突变. 针对这些癌细胞是很困难的,但抑制DNA聚合酶甲基 (Polθ) 通过利用APOBEC3诱导的DNA损伤提供了一个新的策略.
科学领域:
- 分子生物学分子生物学
- 遗传学 遗传学 是一个
- 癌症研究 癌症研究
背景情况:
- APOBEC3 丁脱氨酶是癌症演变的关键驱动因素.
- 用APOBEC3活性向癌细胞是一个重大的临床挑战.
研究的目的:
- 为了确定APOBEC3诱导的双链断裂 (DSBs) 的DNA修复途径.
- 研究在APOBEC3-活性癌症中抑制DNA聚合酶甲基 (Polθ) 的治疗潜力.
主要方法:
- 使用光DSB修复记者和一种新的生物化学分析.
- 从临床瘤样本中分析了基因组数据.
- 进行了体外和体内研究,以评估合成杀伤性.
主要成果:
- 确定了theta介导端连接 (TMEJ) 作为APOBEC3诱导的DSB的主要修复途径.
- 证明了APOBEC3A与RPA竞争,暴露了微同质性,并有利于TMEJ.
- 在瘤中确认了APOBEC3突变足迹,MMD和TMEJ签名的同时发生.
- 显示的Polθ抑制与APOBEC3A诱导的DSB协同作用,导致合成致命性.
结论:
- TMEJ是APOBEC3A诱导的DSB的首选修复机制.
- 聚胺抑制是一种有前途的策略,可以消除具有APOBEC3A活性的癌细胞.
相关概念视频
Translesion DNA Polymerases
11.0K
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...
11.0K
DNA Damage can Stall the Cell Cycle
9.9K
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...
9.9K
DNA Damage Can Stall the Cell Cycle
3.0K
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...
3.0K
Proofreading
8.6K
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...
8.6K
Proofreading
59.7K
Overview
59.7K
Abnormal Proliferation
5.1K
Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
5.1K


