Repression Mechanism


Repressors are regulator proteins that inhibit transcription initiation at gene promoters in order to modulate gene expression in response to variations in environmental conditions. The molecular and biochemical mechanisms by which such repression is achieved vary widely, and are often modulated by signal molecules which act by altering their mechanism of action.

Keywords: DNA looping; contact inhibition; dual regulator; differential contact; activator; steric hindrance

Figure 1.

Strategies of repression of transcription initiation illustrated using paradigm examples. (a) Repression in Escherichia coli of the promoter (P) of the catabolic lac operon by binding of LacI repressor (red) with the operator (O). Active LacI is inactivated by binding of inducer. lacZ, lacY and lacA are the structural genes. (b) Repression in E. coli of the promoter of the anabolic trp operon by the interaction of TrpR repressor (red) with the operator. Normally inactive, TrpR is activated by binding of corepressor (tryptophan). trpE, trpD, trpC, trpB and trpA are the structural genes. (c) Autorepression of the promoter of the bacteriophage λ cI gene by its own protein product. At sufficiently high cellular concentration of cI repressor (red) in a lysogenic strain, the relevant operator is occupied to cause repression. When the cI concentration falls below a critical level, derepression ensues. cro, cII, O and P are structural genes.

Figure 2.

The helix‐turn‐helix motif of a repressor protein and its sequence‐specific interaction with DNA. (a) Schematic representation of the helix‐turn‐helix motif (red) of the bacteriophage λ Cro repressor. α2 is the recognition helix. (b) The two helix‐turn‐helix motifs (red) of a Cro dimer, each bound to half of a DNA operator symmetry. The centres of symmetry are indicated by a diamond. Each α2 lies in a major groove of DNA with sequence‐specific interactions.

Figure 3.

Altering the DNA‐binding specificity of a repressor protein by trading the recognition helix of the helix‐turn‐helix motif. (a) The DNA sequence of the half of Escherichia coli bacteriophage 434 operator (red) and the amino acid sequence of the recognition helix (α2) of the 434 cI repressor (red). The known interacting bonds between the bases in the DNA major groove and the solvent exposed amino acid side‐chains are shown by broken lines. (b) The half of the operator sequence of Salmonella typhimurium bacteriophage P22 (blue) and the corresponding amino acid sequence of the α2 helix of the P22 cI repressor protein (blue). (c) The P22 half operator (blue) and the redesigned α2 helix of the 434 cI repressor. Interaction between the P22 operator and 434 cI repressor was achieved simply by replacing five original surface‐exposed amino acids of 434 cI recognition helix (red) by corresponding amino acids of P22 cI repressor (blue). The hybrid repressor does not bind to the 434 operator.

Figure 4.

The Escherichia coli MetR repressor bound to its operator DNA by a β‐fold motif. Regions of the MetR dimer that contact the operator dyad symmetry are shown. The two β strands (red) occupy a single major groove in the middle of the operator by sequence‐specific interactions.

Figure 5.

Defined steps of transcription initiation by RNA polymerase. All of them, except the last step (promoter clearance), are reversible to different extents depending on the promoter. R, RNA polymerase; P, promoter; (R•P)c, closed complex; (R•P)o, open complex; (R•P)i, initiating complex; (R•P)e, elongating complex. KB, the association constant of (R•P)c formation; kf1, the forward rate constant of isomerization; kf2, the reverse rate constant of isomerization.

Figure 6.

Molecular mechanisms of repressor action. Promoter, open bar; operator, filled bar. (a) Steric hindrance. Because of overlap of the repressor‐ and RNA polymerase‐binding DNA sequences, i.e. the operator and the promoter, repressor (red) binding to the operator sterically hinders binding of (RNP) (yellow) to promoter. The affinity of a repressor to the corresponding operator is higher than that of RNA polymerase to that promoter. (b) Contact inhibition. A DNA‐bound repressor (red) contacts the DNA‐bound RNA polymerase (yellow) and inhibits the activity of the latter. (c) DNA looping. The Escherichia coli gal operon contains two operators, OE and OI, which flank two overlapping promoters located in between. GalR repressor bound to the two operators associates to loop out the intervening promoter DNA segment. DNA looping in the gal operon requires the additional binding of a small histone‐like protein, HU, to a site about midway between OE and OI. DNA looping inhibits the promoter by distorting the DNA.

Figure 7.

Free energy diagrams of open complex formation. ΔGc, ΔGo, and ΔG are the free energies of closed complex (R•P)c formation, open complex (R•P)o formation, and ‘activation’ to transition state (R•P), respectively. (R•P)o is characterized by partial separation of DNA strands. RNA polymerase, yellow icon; repressor, red icon; activator, green icon. (a) Open complex formation by RNA polymerase at a hypothetical promoter. (b) A potential effect of a repressor on open complex formation. (c) A potential effect of an activator on open complex formation.

Figure 8.

Transcription regulation by contact of regulators with RNA polymerase (RNP) (yellow) at a different promoter with a different outcome. (a) Transcription activation by contact between cAMP receptor protein (CRP) (green) bound at position −61.5 and the C‐terminal regions of the α subunit of RNA polymerase (αCTD) at the Escherichia coli lac promoter. (b) Transcription activation by contacts between bacteriophage cI (green) protein bound at position −41.5 and σ subunit of RNA polymerase at Prm of promoter of the cI gene of the phage (autoactivation). In this example, the αCTD (shown by dotted line) very probably occupies the DNA site upstream of the cI‐binding site. (c) Transcription activation by contact between GalR (green) bound at position −60.5 (OE) (position −55.5 with respect to transcription start site) and the αCTD of RNA polymerase at the E. coli galP2 promoter. (d) Transcription repression by contact between GalR (red) bound at position −60.5 (OE) and the αCTD of RNA polymerase at the E. coli galP1 promoter. Note that the variation in the location on DNA of αCTD connected by a flexible hinge to RNA polymerase changes the outcome even for the same regulator (example c versus example d).

Figure 9.

Antagonism of activation. The Escherichia coli deoP2 promoter is fully activated by cAMP receptor protein (CRP) (green) when bound to positions −41 and −93. CytR bound to a position (−61) in between the CRP‐binding sites antagonizes the action of CRP by making contacts with CRP.



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Further Reading

Adhya S (1999) Regulation of gene expression: operons and regulons. In: Lengeler JW, Drews G and Schlegel HG (eds) Biology of the Prokaryotes, pp. 437–468. Stuttgart, Germany: Thieme.

Chamberlin M and Hsu LM (1996) RNA chain initiation and promoter escape by RNA polymerase. In: Lin ECC and Lynch AS (eds) Regulation of Gene Expression in Escherichia coli, pp. 7–25. Austin, TX: RG Landes Co.

Church GM, Sussman JL and Kim SH (1997) Secondary structural complementarity between DNA and proteins. Proceedings of the National Academy of Sciences of the USA 74: 1458–1462.

Gralla JD and Collado‐Vides J (1996) Organization and function of transcription regulatory elements. In: Neidhardt F (ed.) Escherichia coli and Salmonella typhimurium, pp. 1232–1246. Washington DC: ASM Press.

Harrison SC and Agarwal AK (1990) DNA recognition by proteins with helix‐turn‐helix motifs. Annual Review of Biochemistry 59: 933–969.

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Adhya, Sankar(Apr 2001) Repression Mechanism. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1038/npg.els.0000850]