###### Abstract  
Despite decades of intensive research on bacteriophage lambda, a relatively uncharacterized region remains between the _exo_ and _xis_ genes. Collectively, _exo-xis_ region genes are expressed during the earliest stages of the lytic developmental cycle and are capable of affecting the molecular events associated with the lysogenic-lytic developmental decision. In Shiga toxin-producing _E. coli_ (STEC) and enterhebromorgziel _E. coli_ (EHEC) that are responsible for food- and water-borne outbreaks throughout the world, there are distinct differences of _exo-xis_ region genes from their counterparts in lambda phage. Together, these differences may help EHEC-specific phage and their bacterial hosts adapt to the complex environment within the human intestine. Only one _exo-xis_ region protein, Ea8.5, has been solved to date. Here, I have used the AlphaFold and RoseTTAFold machine learning algorithms to predict the structures of six _exo-xis_ region proteins from lambda and STEC/EHEC phages. Together, the models suggest possible roles for _exo-xis_ region proteins in transcription and the regulation of RNA polymerase.  
protein structure; bioinformatics; gene regulation; virus-host relationships; dark-matter 202120211022  
to the bacterium-phage relationship, the human-phage relationship is less characterized but nevertheless, could be an important factor to consider during infection [13]. For example, during _S. aureus_ infections, a phage lysin CBD is able to weaken its hosts on two fronts by simultaneously repressing the expression of bacterial virulence genes and increasing the activity of human macrophages [14]. Aside from Shiga toxin, no other proteins have been identified in Stx\({}^{+}\) phages that modify the human host. Nevertheless, continuing research into human-phage relationships may help drive new therapeutic strategies [15].  
A set of relatively uncharacterized open reading frames (ORFs) between the exonucle-ase gene (_exo_) and the excisionase gene (_xis_) in lambdoid bacteriophages has been shown to affect the lysogenic-lytic developmental decision. These so-called _exo-xis_ region genes tend to produce a greater effect in Stx\({}^{+}\) phages than \(\lambda\), the most studied archetype and logical reference for comparison. Since Stx\({}^{+}\) phages are also known to be more sensitive to prophage induction, the _exo-xis_ region represents a new focal point for understanding how Stx\({}^{+}\) phages adapt to a rapidly changing microenvironment in their hosts and in the human gut [16].  
In bacteria expressing additional copies of the _exo-xis_ region, the overall survival rate is lower [17]. Additional copies of the _exo-xis_ region also increase viral DNA content, corroborating a link to DNA replication that was noted in the first study of the \(\lambda\)_exo-xis_ region [18]. Expression of RecA-dependent SOS response genes are reduced during infection with phages bearing a deletion of the _exo-xis_ region [19]. Since oxidative stress, antibiotic treatment and UV-induced DNA damage all lead to an SOS response [20], the _exo-xis_ region may help the bacteriophage modulate a broad range of stress-associated inputs from its host [21]. The suppressive action of gene expression by the _exo-xis_ region against the bacterial host also affects the transcription of lytic genes [22].  
In this article, I begin by describing the genomic organization of the _exo-xis_ region and then delve further into the structural and functional features of each gene by reviewing the current literature and presenting new molecular models of each gene product if an experimentally determined structure is not known. Further explorations of the _exo-xis_ region have the potential to reveal new insights into the lysogenic-lytic developmental decision and new therapeutic routes to combat infection.