Mechanisms regulating DNA repair processes remain incompletely defined. Here, the circadian factor CRY1, an evolutionally conserved transcriptional coregulator, is identified as a tumor specific regulator of DNA repair. Key findings demonstrate that CRY1 expression is androgen-responsive and associates with poor outcome in prostate cancer. Functional studies and first-in-field mapping of the CRY1 cistrome and transcriptome reveal that CRY1 regulates DNA repair and the G2/M transition. DNA damage stabilizes CRY1 in cancer (in vitro, in vivo, and human tumors ex vivo), which proves critical for efficient DNA repair. Further mechanistic investigation shows that stabilized CRY1 temporally regulates expression of genes required for homologous recombination. Collectively, these findings reveal that CRY1 is hormone-induced in tumors, is further stabilized by genomic insult, and promotes DNA repair and cell survival through temporal transcriptional regulation. These studies identify the circadian factor CRY1 as pro-tumorigenic and nominate CRY1 as a new therapeutic target.

调节DNA修复过程的机制仍未完全确定。在这里，昼夜节律因子CRY1，一种进化上保守的转录共调节子，被确定为DNA修复的肿瘤特异性调节剂。关键发现表明，CRY1表达对雄激素有反应，并与前列腺癌的不良预后相关。功能研究以及CRY1染色体和转录组的首次现场作图表明，CRY1调节DNA修复和G2 / M过渡。DNA损伤可稳定癌症（体外，体内和离体人类肿瘤）中的CRY1，这对于有效的DNA修复至关重要。进一步的机理研究表明，稳定的CRY1暂时调节同源重组所需基因的表达。总的来说，这些发现表明CRY1在肿瘤中是激素诱导的，通过基因组损伤进一步稳定，并且通过暂时的转录调节促进DNA修复和细胞存活。这些研究确定了昼夜节律因子CRY1是促肿瘤的，并提名CRY1作为新的治疗靶标。