When the residues that are involved in RNA binding are plotted on the crystal structures of the archaeal and the human heterodimers, a similar pattern emerges, with residues located in similar positions having comparable effects on the interac- 5 tion with nucleic acids, even when the chemical nature of the residues differ. The RNA-binding residues are clustered along the vertical axis of the elongated Rpb7/E subunit, spanning the length of the molecule from the N-terminal to the C-terminal domain. Within the OB fold, the residues that have the stron- 10 gest impact on RNA binding are located on strands B3, B4 and B5 of the b-barrel. In summary, combining structural information with muta- tional analysis and EMSAs on both the archaeal E subunit and the eukaryotic Rpb7 subunit, we have identiﬁed a putative 15 RNA-binding path along the surface of the Rpb7/E subunit. Most of the residues that have an impact on RNA binding are located on the canonical nucleic acid binding face of the OB fold. Interestingly, the residues contributing to RNA binding in the N-terminal domain are not situated on the front surface of 20 the b-sheet of the truncated RNP domain, the surface normally involved in nucleic acid binding. Recent results have shown that yeast Rpb7 can be UV-crosslinked in a strong and reproducible manner to both strands of promoter DNA, between the TATA box and 25 the start site (26), suggesting that in addition to its function in binding and stabilizing the nascent RNA, Rpb7 has an addi- tional DNA-binding function during transcription initiation. In this scenario, it is possible that the RNA-binding surface we have identiﬁed is also involved in binding DNA during the 30 initiation stage. The human Rpb7 has been shown to interact with a number of transcription factors, some of which are involved in cancer development. Human Rpb7 interacts with the Ewings Sarcoma oncogene DNA-binding domain (27–29) and with the Nepho- 35 blastoma Overexpressed proto-oncogene, which in non- malignant cells is probably involved in the differentiation of several cell types (30). The retinoic acid receptor has been shown to bind to Rpb7 in its unliganded form and repress transcription of a number of transcriptional activators, such as 40 AP-1 (31). Human Rpb7 has also been identiﬁed as a target of the von Hippel-Lindau protein, a component of a ubiquitin ligase E3 complex that acts as potent tumour suppressor and regulates the transcription and secretion of the vascular endothelial growth factor (32). All these data suggest that 45 Rpb4/Rpb7 may mediate the interaction between a number of enhancer transcription factors and the RNA-polymerase core, to regulate gene expression. 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