近日，中国科学院上海生命科学研究院（人口健康领域）冯英研究组的研究成果，以SRSF1 prevents DNA damage and promotes tumorigenesis through regulation of DBF4B Pre-mRNA splicing为题，在线发表在Cell Reports上。该研究揭示了细胞周期相关蛋白DBF4B剪接异构体及剪接调控因子SRSF1在结直肠癌发生发展中的调控作用。
DBF4B是细胞周期S期促进激酶Cdc7的调控因子，与Cdc7激酶一起参与并调控DNA复制的起始与进程，在细胞周期中发挥着重要的调控作用。但DBF4B的不同剪接异构体在肿瘤中的功能及其调控机制，目前尚不清楚。
在研究员冯英的指导下博士生陈琳琳等发现，DBF4B 6号外显子的剪接主要受剪接调控因子SRSF1调控。对DBF4B两种主要的剪接异构体形式进行功能研究，发现DBF4B-FL及SRSF1均能够促进结直肠癌细胞的增殖及体内外成瘤能力，敲减DBF4B-FL及SRSF1可以引起DNA双链断裂，说明其在维持基因组稳定性方面发挥重要作用。在结直肠癌组织中，DBF4B 6号外显子接入增加与SRSF1表达呈正相关。该研究进一步表明DBF4B与SRSF1在结直肠癌发生发展进程中具有重要的生物学意义。
研究工作获得了国家自然科学基金和中科院战略性先导科技专项等的资助。(来源：中国科学院上海生命科学研究院）
SRSF1 Prevents DNA Damage and Promotes Tumorigenesis through Regulation of DBF4B Pre-mRNA Splicing
Summary
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 cellsin vitroand 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.
