Coordinated control of senescence by lncRNA UCA1 and a novel CAPERα/TBX3 co-repressor

Coordination of a complex series of transcriptional, structural and signaling events culminates in cellular senescence, a crucial tumor suppressor mechanism. We have discovered a repressor complex composed of TBX3 and CAPERa which functions upstream of the RB and p53 effector pathways and is required to prevent senescence of primary cells and in mouse embryos. TBX3/ CAPERa directly binds and represses transcription and chromatin structure of genes in multiple senescence pathways and the LncRNA UCA1, which we have identified as a novel tumor suppressor. The TBX3/ CAPERa complex is physically disrupted in oncogene induced senescence, providing a new molecular mechanism for derepression of prosenescence pathways in this system. Our results provide new insight into the oncogenic properties of TBX3, and are the first demonstration of CAPERa and UCA1 function in vivo.

一系列复杂的转录、结构与信号事件的协同调控最终引发细胞衰老（cellular senescence）——这是一类至关重要的肿瘤抑制机制。本研究发现了一种由TBX3与CAPERa组成的阻遏复合物，该复合物作用于RB与p53效应通路的上游，是阻断原代细胞及小鼠胚胎发生细胞衰老的必需因子。TBX3/CAPERa复合物可直接结合并抑制多条衰老通路中的基因以及长链非编码RNA（LncRNA）UCA1的转录与染色质结构，我们已将UCA1鉴定为一种新型肿瘤抑制因子。TBX3/CAPERa复合物在癌基因诱导的衰老过程中发生物理解离，为该系统中促衰老通路的去阻遏提供了全新的分子机制。本研究结果为TBX3的致癌特性提供了全新认知，同时首次证实了CAPERa与UCA1在体内的生物学功能。