SRSF1 Prevents DNA Damage and Promotes Tumorigenesis through Regulation of DBF4B Pre-mRNA Splicing

• Published in: Cell reports (Cambridge) 2017-12, Vol.21 (12), p.3406-3413
• Main Authors: Chen, Linlin, Luo, Chunling, Shen, Lei, Liu, Yuguo, Wang, Qianqian, Zhang, Chang, Guo, Ruochen, Zhang, Yanan, Xie, Zhiqin, Wei, Ning, Wu, Wenwu, Han, Jun, Feng, Ying
• Format: Article
• Language: English
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.11.091

Dysregulated alternative splicing events have been implicated in many types of cancer, but the underlying molecular mechanisms remain unclear. Here, we observe that the splicing factor SRSF1 regulates DBF4B exon6 splicing by specifically binding and promoting its inclusion. Knockdown of the exon6-containing isoform (DBF4B-FL) significantly inhibits the tumorigenic potential of colon cancer cells in vitro and in mice, and SRSF1 inactivation phenocopies DBF4B-FL depletion. DBF4B-FL and SRSF1 are required for cancer cell proliferation and for the maintenance of genomic stability. Overexpression of DBF4B-FL can protect against DNA damage induced by SRSF1 knockdown and rescues growth defects in SRSF1-depleted cells. Increased DBF4B exon6 inclusion parallels SRSF1 upregulation in clinical colorectal cancer samples. Taken together, our findings identify SRSF1 as a key regulator of DBF4B pre-mRNA splicing dysregulation in colon cancer, with possible clinical implications as candidate prognostic factors in cancer patients. [Display omitted] •SRSF1 is a key regulator of DBF4B pre-mRNA splicing•DBF4B-FL and SRSF1 are both required for cancer cell proliferation•DBF4B-FL mediates the effects of SRSF1 in tumorigenesis in mice•These findings have potential clinical implications for cancer development Chen et al. find that SRSF1 is a key regulator of DBF4B pre-mRNA splicing in colon cancer cells and demonstrates that SRSF1 prevents DNA damage and promotes tumorigenesis through its regulation of a DBF4B-FL splice variant.