Fateful Decisions of Where to Cut the Line: Pathology Associated with Aberrant 3′ End Processing and Transcription Termination

[Display omitted] •Poly(A)-signals (PAS) are modular, their usage is influenced by the availability of sequence elements and RNA binding proteins.•In different sequence contexts, PAS sequences with varying usage-efficiencies have evolved.•Throughout development, concentrations and affinities of PAS-binding proteins can change.•PAS-dependent and -independent termination sites are both important to allow for fast gene regulation.•Any change in these evolved equilibria can result in pathologies. Aberrant gene expression lies at the heart of many pathologies. This review will point out how 3′ end processing, the final mRNA-maturation step in the transcription cycle, is surprisingly prone to regulated as well as stochastic variations with a wide range of consequences. Whereas smaller variations contribute to the plasticity of gene expression, larger alternations to 3′ end processing and coupled transcription termination can lead to pathological consequences. These can be caused by the local mutation of one gene or affect larger numbers of genes systematically, if aspects of the mechanisms of 3′ end processing and transcription termination are altered.