Background The long introns of mammals are pools of evolutionary potential due to the multiplicity of sequences that permit the acquisition of novel exons. However, the permissibility of genes to this type of acquisition and its influence on the evolution of cell regulation is poorly understood. Results Here, we observe that human genes are highly permissive to the inclusion of novel exonic regions permitting the emergence of novel regulatory features. Our analysis reveals the potential for novel exon acquisition to occur in over 30% of evaluated human genes. Regulatory processes including the rate of splicing efficiency and RNA polymerase II (RNAPII) elongation control this process by modulating the “window of opportunity” for spliceosomal recognition. DNA damage alters this window promoting the inclusion of repeat-derived novel exons that reduce the ribosomal engagement of cell cycle genes. Finally, we demonstrate that the inclusion of novel exons is suppressed in hematological cancer samples and can be reversed by drugs modulating the rate of RNAPII elongation. Conclusion Our work demonstrates that the inclusion of repeat-associated novel intronic regions is a tightly controlled process capable of expanding the regulatory capacity of cells. Electronic supplementary material The online version of this article (10.1186/s13059-019-1757-5) contains supplementary material, which is available to authorized users.