Naturally occurring stress-induced transcriptional readthrough is a recently 
discovered phenomenon, in which stress conditions lead to dramatic induction of 
long transcripts as a result of transcription termination failure. In 2015, we 
reported the induction of such downstream of gene (DoG) containing transcripts 
upon osmotic stress in human cells, while others observed similar transcripts in 
virus-infected and cancer cells. Using the rigorous methodology Cap-Seq, we 
demonstrated that DoGs result from transcriptional readthrough, not de novo 
initiation. More recently, we presented a genome-wide comparison of NIH3T3 mouse 
cells subjected to osmotic, heat, and oxidative stress and concluded that 
massive induction of transcriptional readthrough is a hallmark of the mammalian 
stress response. In their recent letter, Huang and Liu in contrast claim that 
DoG transcripts result from novel transcription initiation near the ends of 
genes. Their conclusions rest on analyses of a publicly available transcription 
start site (TSS-Seq) dataset from unstressed NIH3T3 cells. Here, we present 
evidence that this dataset identifies not only true transcription start 
sites, TSSs, but also 5'-ends of numerous snoRNAs, which are generally processed 
from introns in mammalian cells. We show that failure to recognize these 
erroneous assignments in the TSS-Seq dataset, as well as ignoring published 
Cap-Seq data on TSS mapping during osmotic stress, have led to misinterpretation 
by Huang and Liu. We conclude that, contrary to the claims made by Huang and 
Liu, TSS-Seq reads near gene ends cannot explain the existence of DoGs, nor 
their stress-mediated induction. Rather it is, as we originally demonstrated, 
transcriptional readthrough that leads to the formation of DoGs.