UC Berkeley

The life of an mRNA molecule is often depicted as a unidirectional flow of discrete stages – transcription by RNA polymerase II (RNAPII), nuclear export, translation, and degradation – with distinct means of regulation occurring at each step. However, a growing body of work has revealed complex crosstalk between stages of this process that is integral to the proper regulation of cellular gene expression. Although such crosstalk often involves compensatory changes to buffer mRNA transcript levels, enhanced transcriptome-wide mRNA decay instigated by viral endonucleases instead causes a global repression of mRNA synthesis. This feedback is not dependent on the specific viral endonuclease but rather hinges on the catalytic activity of host mRNA decay factors. In this regard, a central question is whether this mRNA degradation-transcription feedback loop is unique to viral infection or if it represents a universal response to cellular stress. Early apoptosis has recently been identified as a context in mRNA transcripts are globally degraded. To test whether apoptosis-driven mRNA decay causes transcriptional repression, steady-state and nascently transcribed RNA were measured concurrently in the presence or absence of a death-inducing ligand. Global RNAPII transcription is reduced during early apoptosis in a manner dependent on mitochondrial outer membrane permeabilization-induced mRNA decay by cytoplasmic 3’-end decay factors. Chromatin immunoprecipitation (ChIP) experiments revealed that this apoptotic transcriptional defect elicited by 3’-end mRNA decay is associated with impaired RNAPII recruitment to promoters. Cytoplasmic RNA binding proteins (RBPs), such as PABPC, increase in nuclear localization during apoptotic mRNA decay. Blocking nuclear import severs the link between cytoplasmic mRNA decay and transcription in both the viral endonuclease and apoptosis contexts, suggesting that it is the transport of RBPs from the cytoplasm to the nucleus that links these two processes. These observations point to a mode of gene regulation in which enhanced mRNA leads to a further shutdown in mRNA transcription, representing a conserved cellular response to intrinsic or extrinsic threats.