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Summary: The interplay of transcription, topological tension, and chromosome breakage is a subject of intense interest, but, with so many facets to the problem, it is difficult to test. Here, we vary the orientation of promoters relative to one another in a yeast system that permits sensitive detection of chromosome breaks. Interestingly, convergent transcription that would direct RNA polymerases into one another does not increase chromosome breakage. In contrast, divergent transcription that would create underwound and potentially single-stranded DNA does cause a marked increase in chromosome breakage. Furthermore, we examine the role that topoisomerases are playing in preventing genome instability at these promoters and find that Top2 is required to prevent instability at converging promoters. : Pannunzio and Lieber demonstrate that, in wild-type cells, divergent, but not convergent, transcription increases genome instability measured by gross chromosomal rearrangements. For convergent promoters, the function of topoisomerase II is critical for preventing instability at convergent promoters.