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2018年10月31日，全球自然科学三大旗舰期刊之一、英国《自然》正刊在线发表美国哈佛大学医学院、达纳法伯癌症研究所、罗格斯大学新泽西癌症研究所、哈佛大学与麻省理工学院布罗德研究所、加拿大魁北克中心医院、拉瓦尔大学癌症研究中心、法国图卢兹第三大学的研究报告，通过细菌基因组编辑技术CRISPR发现了乳腺癌易感基因BRCA1突变癌细胞耐药的新机制。 BRCA1为重要的抑癌基因之一，一旦发生突变，容易引起乳腺癌和卵巢癌。基因，即携带蛋白质编码的脱氧核糖核酸DNA，癌细胞DNA被抗癌药物损伤后，DNA末端切除是重要的癌细胞DNA修复机制，而癌细胞DNA末端切除受限，是BRCA1突变癌细胞DNA同源重组修复受阻的关键。该研究利用CRISPR对功能丧失进行筛查，确定动力蛋白轻链DYNLL1为DNA末端切除的抑制因子。DYNLL1缺失后，BRCA1突变癌细胞的DNA末端切除和同源重组得到恢复，从而诱发对铂类药物和多腺苷二磷酸核糖聚合酶PARP抑制剂的耐药。BRCA1低表达与癌细胞染色体畸变增加相关，并且体细胞基因结构突变连接序列表明同源重组减少。BRCA1低表达癌的DYNLL1表达同时减少，可以减少基因组变化，并且增加病变的同源重组。细胞实验表明，DYNLL1与DNA末端切除相关蛋白质（DNA双链断裂修复蛋白MRE11、DNA修复蛋白RAD50、重组蛋白NBS1的MRN复合物，布卢姆综合征蛋白质BLM解旋酶，DNA2核酸内切酶）结合，可以限制DNA末端的核苷酸链水解。体外实验表明，DYNLL1直接与DNA双链断裂修复蛋白MRE11结合，可以限制其DNA末端切除活性。 因此，该研究结果表明，DYNLL1是癌细胞DNA末端切除和重组修复的重要抑制因子，可以影响基因组稳定性、提高化疗药物或PARP抑制剂破坏癌细胞DNA的效果。 对此，美国德克萨斯大学MD安德森癌症中心肿瘤生物学教授凯瑟琳·施拉赫发表同期报道：癌症耐药新发现。 Nature. 2018 Oct 31. [Epub ahead of print] DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells. Yizhou Joseph He, Khyati Meghani, Marie-Christine Caron, Chunyu Yang, Daryl A. Ronato, Jie Bian, Anchal Sharma, Jessica Moore, Joshi Niraj, Alexandre Detappe, John G. Doench, Gaelle Legube, David E. Root, Alan D. D'Andrea, Pascal Drané, Subhajyoti De, Panagiotis A. Konstantinopoulos, Jean-Yves Masson, Dipanjan Chowdhury. Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; CHU de Québec Research Center, HDQ Pavilion, Oncology Axis, Québec City, Québec, Canada; Laval University Cancer Research Center, Québec City, Québec, Canada; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA; Université de Toulouse, UT3, Toulouse, France. Limited DNA end resection is the key to impaired homologous recombination in BRCA1-mutant cancer cells. Here, using a loss-of-function CRISPR screen, we identify DYNLL1 as an inhibitor of DNA end resection. The loss of DYNLL1 enables DNA end resection and restores homologous recombination in BRCA1-mutant cells, thereby inducing resistance to platinum drugs and inhibitors of poly(ADP-ribose) polymerase. Low BRCA1 expression correlates with increased chromosomal aberrations in primary ovarian carcinomas, and the junction sequences of somatic structural variants indicate diminished homologous recombination. Concurrent decreases in DYNLL1 expression in carcinomas with low BRCA1 expression reduced genomic alterations and increased homology at lesions. In cells, DYNLL1 limits nucleolytic degradation of DNA ends by associating with the DNA end-resection machinery (MRN complex, BLM helicase and DNA2 endonuclease). In vitro, DYNLL1 binds directly to MRE11 to limit its end-resection activity. Therefore, we infer that DYNLL1 is an important anti-resection factor that influences genomic stability and responses to DNA-damaging chemotherapy. DOI: 10.1038/s41586-018-0670-5 Nature. 2018 Oct 31. [Epub ahead of print] A new road to cancer-drug resistance. Katharina Schlacher. The discovery of a mechanism that leads to cancer-therapy resistance highlights the many ways that tumour cells can adapt to survive — and reveals the limitations of categorizing patients by their gene mutations. DOI: 10.1038/d41586-018-07188-1
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