RAD51 在转录和功能水平上的调控：癌症治疗的前景如何？,Cancers

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RAD51 在转录和功能水平上的调控：癌症治疗的前景如何？
Cancers ( IF 4.5 ) Pub Date : 2021-06-11 , DOI: 10.3390/cancers13122930
Esin Orhan ₁ , Carolina Velazquez ₂ , Imene Tabet ₁ , Claude Sardet ₁ , Charles Theillet _{1,

2}

Affiliation

RAD51 重组酶是同源重组 (HR) 的关键效应子，同源重组是双链断裂的重要 DNA 修复机制。RAD51 蛋白被 BRCA2 招募到 DNA 断裂处，并形成同聚丝，侵入同源染色单体并将其用作修复模板。RAD51 细丝可通过免疫荧光检测为细胞核中的独特焦点，它们的存在可以读出 HR 熟练程度。RAD51 是一种重要基因，可保护细胞免受遗传不稳定的影响。它的表达在正常细胞中较低且受到严格调节，相反，在大部分癌症中表达升高，其表达水平和活性与对基因毒性治疗的敏感性有关。特别是，BRCA 缺陷型肿瘤表现出 RAD51 灶形成减少或消失，以及对铂盐或 PARP 抑制剂的敏感性增加。然而，对治疗的抵抗很快就会出现，并且通常基于 RAD51 病灶形成的完全或部分恢复。因此，RAD51 可能是一个非常有价值的治疗靶点。在这里，我们回顾了影响 RAD51 基因转录的多个调控水平，以及决定其表达水平的翻译后修饰、DNA 损伤位点的招募以及同丝的有效形成。其中一些调节水平可能是有针对性的，并讨论了它们对癌细胞存活的影响。

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Regulation of RAD51 at the Transcriptional and Functional Levels: What Prospects for Cancer Therapy?

The RAD51 recombinase is a critical effector of Homologous Recombination (HR), which is an essential DNA repair mechanism for double-strand breaks. The RAD51 protein is recruited onto the DNA break by BRCA2 and forms homopolymeric filaments that invade the homologous chromatid and use it as a template for repair. RAD51 filaments are detectable by immunofluorescence as distinct foci in the cell nucleus, and their presence is a read out of HR proficiency. RAD51 is an essential gene, protecting cells from genetic instability. Its expression is low and tightly regulated in normal cells and, contrastingly, elevated in a large fraction of cancers, where its level of expression and activity have been linked with sensitivity to genotoxic treatment. In particular, BRCA-deficient tumors show reduced or obliterated RAD51 foci formation and increased sensitivity to platinum salt or PARP inhibitors. However, resistance to treatment sets in rapidly and is frequently based on a complete or partial restoration of RAD51 foci formation. Consequently, RAD51 could be a highly valuable therapeutic target. Here, we review the multiple levels of regulation that impact the transcription of the RAD51 gene, as well as the post-translational modifications that determine its expression level, recruitment on DNA damage sites and the efficient formation of homofilaments. Some of these regulation levels may be targeted and their impact on cancer cell survival discussed.

更新日期：2021-06-11

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