## 1 Introduction  
Transcription, the initial stage of gene expression, is intricately regulated. This regulation is vital for the coordination of transcription with other cellular processes and, ultimately, for the successful adaptation of the cell to the environment. RNA polymerase (RNAP), the enzyme of transcription, is a direct target for binding by multiple regulators that act on key RNAP domains. For example, NusA binds to the N-terminal coiled-coil element of the \(\beta\)' protein, the same region on the RNAP core as bound by \(\sigma^{70}\)[1], in order to assist the transition from initiation to elongation. NusG, its bacterial homologue RfaH, and their eukaryotic homologue Spt5 bind at the \(\beta\)' clamp [2, 3, 4] across the central cleft of RNAP, fixing the clamp domain in the closed conformation and, therefore, increasing the processivity of elongation. The transcription repair coupling factor Mfd binds near the upstream opening of the RNAP primary channel and acts as an anti-arrest factor by promoting forward translocation, which can ultimately result in displacement of stalled RNAP from the DNA template [5, 6]. A distinct group of transcription factors bind at an area referred to as the secondary channel (Figure 1 and Table 1), located approximately on the opposite side of the RNAP to the binding site of the aforementioned factors. The RNAP secondary channel is a narrowing tunnel leading directly from the enzyme surface to its catalytic center (Figure 1A). This secondary channel is proposed as the main path for NTP entry into the center [7, 8] and is also known to accommodate the 3' end of the RNA during polymerase backtracking [9, 10]. Secondary channel-binding factors (SCBFs) are present in all three kingdoms of life--bacteria [11, 12], archaea [13] and eukaryotes [14]. Below we will focus on the bacterial SCBFs; a group of factors that appear to be related to one another, but are evolutionarily unrelated to the eukaryotic/archaeal SCBFs. Bacterial SCBFs share a similar structural fold (Figure 1B). They are small proteins with a globular C-terminal domain, responsible for binding to RNAP, and a coiled-coil domain, which, at least for some of SCBFs, has been shown to be inserted through the secondary channel to modulate transcription. Two functionally important acidic residues are typically located at the tip of this domain. The SCBFs can be roughly divided into three functional groups; the GreA/B group, the DksA group, and factors with unknown function. The precise repertoire of factors differs extensively between bacterial species, and may depend on the lifestyle and environmental niche of the bacterium. For example, at least five SCBFs have been identified in _E. coli_: GreA, GreB, DksA, TraR and Rnk. The mechanisms of _in vitro_ RNAP modulation by GreA, GreB, DksA, and their _in vivo_ functions, have been extensively studied [11, 15, 16]. TraR belongs to the DksA family, but its exact regulatory mechanism remains obscured [17]; the function of Rnk is currently unknown [18]. Most bacteria have fewer SCBFs than _E. coli_, and some bacteria with smaller genomes have GreA as their sole SCBF [19]. None of the _E. coli_ SCBFs are essential for cells in normal growth conditions, although deletion of several SCBFs makes the cells sick ([20, 21], and see below). At least some physiological functions of SCBFs appear to be redundant in this species. For example, overexpression of GreB compensates for the deletion of DksA [15], despite their different activities _in vitro_. The importance of SCBFs becomes apparent when a single SCBF is coded in the genome. For example, the single SCBF, GreA in both _Mycoplasma genitalium_, which has one of the smallest genome amongst bacteria [22], and its close relative _Mycoplasma pneumoniae_[23], is essential. Cells of _Streptococcus pneumoniae_ (_S. pneumoniae_), which also has GreA as its sole SCBF, become extremely sick when GreA is deleted ([24], see below).