非依赖BRCA1/53BP1的DNA双链断裂损伤修复通路致乳腺癌放疗抵抗的研究

Radiotherapy is one of the important means of treatment of breast cancer, the radiation resistance is closely related to the DNA damage response mechanism. The study found that radiation induced by double-stranded DNA rupture is by homologous recombination and non-homologous end link way to be repaired, BRCA1 protein and 53 bp1, respectively played an important role in the above two pathways. Pilot study, we find that understanding different, 53 bp1 in cell defects in BRCA1 knock out further loss not only make the cell DSB repair ability, on the contrary make tumor cell DNA damage repair ability to recover, radiation resistance. At that: there is not dependent on 53 bp1 BRCA1 / double bond fracture damage of DNA repair pathways cause breast cancer radiotherapy resistance? Studied in this paper on the basis of previous work, the use of proteomics, molecular biology, cell biology, biochemistry and bioinformatics methods, the research is not dependent on the BRCA1/53 bp1 DSB repair pathways, and the DNA damage response caused by radiation (stagnation of the cell cycle, damage repair and/or apoptosis) role. The research results will fill the current understanding of DNA damage in breast cancer radiotherapy resistance of blank, to promote the development of DNA damage repair field and the related clinical application is of great significance.

乳腺癌放射线抵抗与DNA损伤应答机制密切相关，BRCA1和53BP1蛋白分别在同源重组和非同源末端链接途径中扮演重要角色。我们前期研究发现：在BRCA1缺陷细胞中敲除53BP1不仅不会使细胞DSB修复能力进一步丧失，反而使肿瘤细胞DNA损伤修复能力得到恢复，产生放疗抗性。同时，有研究报道在BRCA1缺陷细胞中抑制53BP1使细胞对ATM抑制剂敏感性增加。我们由此推测：细胞中是否存在着一条依赖于ATM但并不依赖于BRCA1/53BP1的DNA双链断裂损伤修复的未知“备用”信号通路，在DSB主要修复通路受阻后发挥替代作用以最大程度上保持细胞活性？！本研究拟以前期工作为基础，探讨不依赖于BRCA1/53BP1的DSB修复通路，及其在放射线引起的DNA损伤应答中的作用。该研究结果将填补目前对DNA损伤应答在乳腺癌放疗抗性中认识的空白，对推进DNA损伤修复领域的发展及与此相关的临床应用具有重要意义。

乳腺癌放射线抵抗与DNA损伤应答机制密切相关，BRCA1和53BP1蛋白分别在同源重组和非同源末端链接途径中扮演重要角色。我们以前期工作为基础，构建了BRCA1/53BP1缺陷型乳腺癌细胞系，同时发现在BRCA1缺陷细胞中敲除53BP1使得肿瘤细胞DNA损伤修复能力得到恢复，产生放疗抗性。后续研究将着重阐明不依赖于BRCA1/53BP1的DSB修复通路，及其在放射线引起的DNA损伤应答中的作用。该研究结果将填补目前对DNA损伤应答在乳腺癌放疗抗性中认识的空白，对推进DNA损伤修复领域的发展及与此相关的临床应用具有重要意义。