Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Genome Stability Laboratory, CHU de Québec Research Center, HDQ Pavilion, Oncology Axis, Québec City, Québec, Canada.
Nature. 2018 Nov;563(7732):522-526. doi: 10.1038/s41586-018-0670-5. Epub 2018 Oct 31.
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.
DNA 末端切除有限是 BRCA1 突变型癌细胞中同源重组受损的关键。在这里，我们使用功能丧失 CRISPR 筛选，鉴定出 DYNLL1 是 DNA 末端切除的抑制剂。DYNLL1 的缺失可促进 DNA 末端切除，并恢复 BRCA1 突变细胞中的同源重组，从而诱导对铂类药物和聚（ADP-核糖）聚合酶抑制剂的耐药性。BRCA1 表达水平低与原发性卵巢癌中染色体畸变增加相关，体细胞结构变异的连接序列表明同源重组减少。在 BRCA1 表达水平低的癌中，DYNLL1 的表达同时降低可减少基因组改变并增加病变处的同源性。在细胞中，DYNLL1 通过与 DNA 末端切除机制（MRN 复合物、BLM 解旋酶和 DNA2 内切酶）结合来限制核酶对 DNA 末端的降解。在体外，DYNLL1 直接结合 MRE11 以限制其末端切除活性。因此，我们推断 DYNLL1 是一个重要的抗切除因子，影响基因组稳定性和对 DNA 损伤化疗的反应。
