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 Leader Sequence
SK Samal, University of Maryland, College Park, MD, USA
© 2013 Elsevier Inc. All rights reserved.

This article is a revision of the previous edition article by PS Lovett, volume 2, pp 1078–1079, © 2001, Elsevier Inc.

Glossary Preinitiation complex A promoter-based complex of an

A cap It is the structure at the 5′ end of eukaryotic RNA polymerase and initiation protein competent to
messenger RNA (mRNA) and is introduced after initiate transcription.
transcription by linking the terminal phosphate of 5′ Repressor A protein that inhibits expression of a gene. It
guanosine triphosphate (GTP) to the terminal base of the may act to prevent transcription by binding to an operator
mRNA. The added G and sometimes other bases are site in DNA or to prevent translation by binding to RNA.
methylated. Splicing The precise ligation of blocks of noncontiguous
Coding sequence The sequence of a gene that represents a coding sequences (exons) in cellular or viral pre-mRNAs
protein sequence. with excision of the intervening noncoding sequences
Genome Total genetic information carried by a cell or (introns).
organism. Transcription attenuation A mechanism that depends
Negative sense The sense of DNA or RNA that is upon the ability of external circumstances to influence
complementary in sequence to the positive sense, or the ribosome movement in the leader region.
coding sense. Translation attenuation A mechanism that controls the
Operon A unit of bacterial gene expression and ability of RNA polymerase to read through an attenuator,
regulation, including structural genes and control which is an intrinsic terminator located at the beginning
elements in DNA, recognized to regulate gene product(s). of a transcription unit.

The messenger RNA (mRNA) region that precedes the coding entering the structural genes of an operon. Transcription ter­
sequence for a gene is called the ‘leader sequence’. This region mination is relieved when the intracellular concentration of
is also known as the ‘five prime untranslated region (5′ UTR)’ the end-product amino acid of the operon-specified enzymes
(Figure 1). It begins at the +1 position (where transcription falls below some minimal level. The level of the end-product
starts) and ends one nucleotide before the start codon of the amino acid is sensed by the translation of a short­
coding region. Leader sequences have the propensity for form­ leader-encoded open reading frame (ORF) immediately
ing secondary structures (stem-loops) by base pairing of upstream of the transcription termination signal; the ORF
complementary sequences. In prokaryotes, the leader contains one or more codons for the operon end-product
sequences are usually short. In eukaryotes and viruses, the amino acid. Low intracellular levels of the end-product
leader sequences may vary from few nucleotides to several amino acid prevent high-level charging of the cognate transfer
hundred nucleotides. It usually contains the site for ribosome RNA (tRNA), resulting in ribosomal pausing at leader codons
binding. At times, the leader sequence may be translated into for the end-product amino acid. The paused ribosome inter­
a short-leader peptide, which can affect the transcription of feres with the secondary structure of the transcription
the rest of the mRNA. terminator causing the formation of a second configuration
Leader sequences can regulate downstream expression at the in the mRNA, the attenuator, which allows transcription to
levels of transcription or translation in bacteria and can mod­ enter the downstream operon-coding sequence.
ulate downstream translation in eukaryotes. Leader sequences Transcription antitermination involves the formation of a
in viruses can play an important role in the regulation of gene transcription termination structure in leader mRNA, which is
expression, replication, and pathogenicity. Mutations in the either inhibited or facilitated by the interaction of a protein (or
leader sequences of cellular mRNAs can have implications for a tRNA molecule) with leader mRNA sequences. For example,
disease and tumorigenesis. the trp RNA-binding attenuation protein (TRAP) plus trypto­
phan binds to the leader sequence of the Bacillus subtilis trp
operon causing the formation of a transcription terminator.
Transcription in Bacteria In the absence of tryptophan, TRAP fails to bind to the leader
sequence and an antiterminator structure forms allowing tran­
Transcription attenuation comprises one level of regulation scription to enter the operon. Other operons that follow this
for many amino acid biosynthetic operons in enteric bacteria. general pattern of regulation include the bgl operon of
Nucleotide sequences within the leader cause the formation Escherichia coli, the pur, pyr, hut, lic, and glp operons and the
of a domain of secondary structure which acts as a tran­ sac regulon of B. subtilis, the ami operon of Pseudomonas, and the
scription termination signal for bacterial RNA polymerase. nas regulon of Klebsiella. Aminoacyl-tRNA synthetases in
Transcription initiated in the upstream promoter terminates Gram-positive bacteria are also regulated by antitermination.
within the leader so as to prevent RNA polymerase from The uncharged tRNA interacts with the leader sequences to

Brenner’s Encyclopedia of Genetics, 2nd edition, Volume 4 doi:10.1016/B978-0-12-374984-0.00850-0 203

204 Leader Sequence

Poly-A
Cap 5′UTR Coding sequence 3′UTR
Start Stop tail

5′ 3′
Figure 1 The structure of a typical human protein-coding mRNA, including the untranslated regions (UTRs).

promote the formation of an antiterminator structure allowing structure or decreased recognition of IRPs, leading to human
transcription to enter the tRNA synthetase-coding sequence. disease.
2. Structured 5′ UTRs and translation inhibition. Around
10% of all mRNAs contain unusually long 5′ UTRs. Many of
Translation in Bacteria those mRNAs encode proto-oncogenes or genes whose protein
products are implicated in cell growth. These long 5′ UTRs give
Translation attenuation regulates several antibiotic-inducible, the propensity for formation of stable secondary structure that
antibiotic-resistance genes (e.g., cat, erm). A domain of second­ may inhibit translation initiation by blocking the progress of
ary structure in leader mRNA sequesters the ribosome-binding the scanning ribosome. These structured mRNAs are particu­
site for the downstream resistance determinant, preventing larly dependent on the activity of the cap-dependent
translation initiation. Antibiotic-induced ribosome stalling in unwinding machinery for their translation. Since many of
a short ORF within the leader causes destabilization of the these structured RNAs are associated with growth control,
secondary structure, which frees the ribosome-binding site mutation in the 5′ UTR of these mRNAs can cause overexpres­
allowing translation of a coding sequence whose protein pro­ sion of the protein product leading to tumor genesis.
duct can neutralize the antibiotic. 3. Internal ribosome entry site (IRES). Certain eukaryotic
Translational repression is well exemplified by certain oper­ mRNAs contain an internal ribosome entry site (IRES) prior
ons encoding bacterial ribosomal proteins. The translational to the coding sequence. An IRES presumably functions in an
repressor is a single ribosomal protein encoded by the operon; analogous manner to a bacterial ribosome-binding site in
the nonregulatory function of this protein is to act as a struc­ allowing translation initiation by directly serving as a
tural component of the ribosome. In several examples, the ribosome-binding target. The presence of an IRES preceding a
binding target for the repressor protein in the operon leader coding sequence in a eukaryotic mRNA enables an mRNA that
sequence mimics the structure or sequence of the ribosomal is not capped to be translated.
RNA (rRNA) target for the same protein. Binding of the regu­ IRESs are responsible for translation of many viral and
latory protein to leader mRNA is presumably of lower affinity cellular mRNAs with clinical relevance in humans. Mutations
than that for rRNA binding in vivo. Leader binding by the in the region of the IRES have been found to influence the
repressor interferes with translation of operon mRNA by translational efficiency of the mRNA.
occluding the ribosome-binding site or by changing the sec­
ondary structure of leader.

Transcription and Translation of Viral mRNAs

Translation in Eukaryotes The 5′ UTRs of viral mRNAs have been shown to play impor­
tant roles in the regulation of viral transcription and
Translation in eukaryotes is typically initiated by the scanning
translation. In influenza A virus, 5′ UTR contains the signals
of a 40S ribosomal preinitiation complex. Scanning begins at
responsible for RNA replication, transcription, and packaging.
the 5′-capped end of the mRNA and halts at the first initiator
The 5′ UTR of all picorna virus genomes contains IRES that
codon, usually AUG, where translation begins. There are a
directs cap-independent internal initiation of protein synthesis.
number of ways in which structural elements in the 5′ UTR of
The 5′ UTR present in all of the late adenovirus mRNAs are
mRNAs can influence the translation of the downstream ORF.
termed ‘tripartite leader sequence (TPL)’. TPL is formed by the
1. Regulation of transcription by small structural elements. splicing of three exons. TPL facilitates mRNA transport and
Small structural elements in the 5′ UTR can affect the transla­ accumulation in the cytoplasm and is responsible for the selec­
tion of certain mRNAs. For example, a stem–loop structure of tive translation of the late viral proteins in preference to the
around 30 nucleotides formed the iron-response element cellular proteins. All of the coronavirus mRNAs contain iden­
(IRE), which regulates translation of mRNAs that are responsi­ tical leader sequences, which are derived from the 5′ end of the
ble for iron storage and metabolism. There are two related genomic RNA. Coronavirus leader RNA regulates and initiates
cytoplasmic iron-regulatory proteins (IRP1 and IRP2) that mRNA transcription. The 5′ leader sequence of retrovirus RNA
bind to this element. Under conditions of iron deprivation, is involved in a variety of functions that include RNA elonga­
these proteins bind to the IRE and block the binding of transla­ tion, RNA splicing, protein translation, genomic RNA
tion preinitiation complex, which inhibits translation of dimerization and packaging, and initiation of reverse transcrip­
downstream ORF. Under conditions of iron plentiful, these tions. The 3′ end of the genome of nonsegmented
proteins undergo posttranslational modifications that cause negative-sense RNA viruses is also known as the leader
inactivation and degradation by proteosome. Mutations in sequence that acts as a promoter for transcription and replica­
the sequence of IRE can lead to decreased stability of the tion of the viral genome.
 Leader Sequence 205

Landick R, Turnbough CL, Yanofsky C, et al. (1996) Transcriptional attenuation. In:

See also: Open Reading Frame; Transcription; Translation. Neidhardt FC, et al., Escherichia coli and Salmonella, 2nd edn., American Society for
Microbiology, Washington, DC, 1263–1286.
Lovett PS Rogers EJ (1996) Ribosome regulation by the nascent peptide.
Microbiological Reviews 60: 366–385.
Further Reading Molhoj M and Dal Degan F (2004) Leader sequences are not signal peptides. Nature
Biotechnololgy 22: 1502.
Henkin TM (2000) Transcription termination in bacteria. Current Opinion in Nakamoto T (2009) Evolution and the universality of the mechanism of initiation of
Microbiology 3: 149–153. protein synthesis. Gene 432: 1–6.
Hinnebusch A (1994) Translational control of GCN4: An in vivo barometer of Pickering BB and Willis AE (2005) The implications of structured 5′ untranslated regions
initiation-factor activity. Trends in Biochemical Sciences 19: 409–414. on translation and disease. Seminars in Cell and Development Biology 16: 39–47.