放化疗是肿瘤治疗的主要手段，但放化疗抵抗仍是肿瘤治疗的难题。由于放疗和部分化疗药物主要靶向快速增殖细胞的DNA，DNA损伤修复的异常被认为是肿瘤治疗抵抗的重要原因,但机制仍待阐明。我们前期发现含有BRCT结构域的蛋白ECT2蛋白的表达与鼻咽癌和肺癌治疗复发呈显著负相关。ECT2在放化疗抵抗肿瘤细胞系中均呈低表达，而在放化疗敏感肿瘤细胞及病人样本中呈高表达。在功能上，我们发现ECT2蛋白参与核仁转录依赖的DNA损伤调控，抑制同源重组修复，促进非同源末端连接，且受ATM和RNA聚合酶I共同调节。进一步，我们发现ECT2与DNA损伤修复中的关键分子PARP1, RFC1相互作用。在DNA损伤条件下，ECT2的低表达促进了PARP1与DNA的结合，抑制核仁转录和复制。据此，我们提出：ECT2的低表达促进核仁DNA损伤的同源重组修复效率，促进PARP活性，抑制细胞转录和复制，导致放疗抵抗。

Radiotherapy and chemotherapy are the regular modalities for cancer treatment, however resistance still presents as the major obstacle for efficient treatment. Radiotherapy delivered by ion-irradiation preferably targets replicated DNA to induced irreversible DNA damage. Aberrant DNA damage repair has emerged as one of the critical factors that leads to radiotherapy resistance, however, mechanism underlying remains largely unknown. In this study, we find that BRCT domain family member, ECT2 is negatively correlated with the recurrence of nasopharyngeal carcinoma and lung cancer. Lower expressions of ECT2 are found both in radiotherapy resistant cancer cell lines and patient samples compared to sensitive cells and patient samples. Mechanistically, we found that ECT2 is involved transcription-dependent DNA damage repair in nucleolar in ATM-RNA polymerase I dependent manner. High expression of ECT2 inhibits homologous recombination repair and promotes non-homologous end joining. More importantly, we found that ECT2 interacts with PARP1, which are critical modulators in DNA damage repair. Low expression of ECT2 promotes the DNA binding affinity of PARP1 and inhibits nucleolar transcription and replication under DNA damage. Based on this, we propose low expression of ECT2 causes radiotherapy resistance by regulation of PARP1. The more efficient homologous recombination repair and higher PARP activity after DNA damage by ECT2 deprivation inhibit transcription and replication in nucleolar, subsequently protecting cancer cell from radiation attack.