Neurogenesis can be inhibited by Cytosine beta-D-arabinofuanoside (Ara-C). How does Ara-C work?
阿糖胞苷（Ara-C）可以抑制神经发生。Ara-C 的作用机制是什么？

Question

BlackTom AI · Accepted Answer

Ara-C (cytarabine) is a cytosine nucleoside analog whose cytotoxicity derives from being metabolically activated and incorporated into DNA, thereby blocking DNA replication and producing strand breaks.

Relevant concepts:
- Nucleoside analog activation: Ara-C is taken up by cells and phosphorylated by deoxycytidine kinase to Ara-C monophosphate, then to Ara-CDP and the active triphosphate Ara-CTP.
- DNA incorporation and replication interference: Ara-CTP is a substrate for DNA polymerases and becomes incorporated into nascent DNA, where the arabinose sugar causes steric and conformational defects that impede elongation.
- Replication stress and topoisomerase I (Topo I): Stalled replication forks and altered DNA structure promote formation of Topo I cleavage complexes; when DNA containing Ara-C is processed by Topo I, religation is impaired, stabilizing cleavage complexes and producing single- and double-strand breaks that lead to DNA fragmentation and cell death.
- Cell-cycle specificity: Because Ara-C affects DNA synthesis, proliferating cells (e.g., neural progenitors during neurogenesis) are particularly vulnerable.

Step-by-step mechanism:
1. Ara-C enters dividing neural progenitors.
2. Cellular kinases convert Ara-C → Ara-CTP (active form).
3. Ara-CTP is incorporated into DNA by DNA polymerases during S phase.
4. Incorporation perturbs DNA elongation and causes fork stalling.
5. Topo I, acting to relieve torsional stress, cleaves the altered DNA but cannot efficiently religate it when Ara-C is present, forming stabilized cleavage complexes.
6. Accumulation of these complexes causes DNA fragmentation, triggering apoptosis and thus inhibiting neurogenesis.

Why the correct answer is correct:
Option 2 precisely describes this pathway: incorporation into DNA and formation of Topo I cleavage complexes that result in fragmentation and inhibition of DNA replication.

Why the other options are incorrect:
- Option 1 (increase neuron-specific RNase) is not how Ara-C acts; it targets DNA synthesis, not by upregulating RNases.
- Option 3 (redox/superoxide generation) describes oxidative toxin mechanisms, not Ara-C’s principal mode of action.
- Option 4 (binding DNA to block transcription) fits transcription inhibitors (e.g., actinomycin D) rather than nucleoside analogs that block DNA replication.

Conclusion: The correct mechanism is that Ara-C is incorporated into DNA and inhibits replication by forming cleavage complexes with topoisomerase I, resulting in DNA fragmentation, matching the provided answer.

Neurogenesis can be inhibited by Cytosine beta-D-arabinofuanoside (Ara-C). How does Ara-C work? 阿糖胞苷（Ara-C）可以抑制神经发生。Ara-C 的作用机制是什么？单项选择题

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Neurogenesis can be inhibited by Cytosine beta-D-arabinofuanoside (Ara-C). How does Ara-C work?

Neurogenesis can be inhibited by Cytosine beta-D-arabinofuanoside (Ara-C). How does Ara-C work? 阿糖胞苷（Ara-C）可以抑制神经发生。Ara-C 的作用机制是什么？

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