Transcriptional adaptation: where mRNA decay meets genetic compensation

Nonsense-mediated mRNA decay (NMD) is a translation-coupled quality control mechanism that safeguards cells against faulty transcripts that could lead to truncated and potentially harmful proteins. However, we posit that there is another side to NMD: it does not just clear away defective transcripts, it also triggers a form of genetic compensation known as transcriptional adaptation (TA). This recently discovered cellular response operates independently of protein loss. Instead, mutant mRNA decay can lead to the upregulation of functional paralogs, thereby compensating for the loss of the mutated gene. Consequently, TA could play a prominent role in genotype-phenotype correlations in human genetic diseases. • Transcriptional adaptation (TA) is a recently discovered mode of genetic compensation that relies on mRNA decay. • TA occurs across various species, including humans. • TA plays a role in human genetic disorders. • CRISPR-Cas9-induced mutations, splice-switching ASOs, and self-cleaving ribozymes can induce TA by triggering mRNA decay.