Restriction enzyme

A restriction enzyme, restriction endonuclease, or restrictase is an enzyme that cleaves DNA

into fragments at or near specific recognition sites within molecules known as restriction
sites.[1][2][3] Restriction enzymes are one class of the broader endonuclease group of enzymes.
Restriction enzymes are commonly classified into five types, which differ in their structure and
whether they cut their DNA substrate at their recognition site, or if the recognition and cleavage
sites are separate from one another. To cut DNA, all restriction enzymes make two incisions,
once through each sugar-phosphate backbone (i.e. each strand) of the DNA double helix.

These enzymes are found in bacteria and archaea and provide a defense mechanism against
invading viruses.[4][5] Inside a prokaryote, the restriction enzymes selectively cut up foreign DNA
in a process called restriction digestion; meanwhile, host DNA is protected by a modification
enzyme (a methyltransferase) that modifies the prokaryotic DNA and blocks cleavage. Together,
these two processes form the restriction modification system.[6]

More than 3,600 restriction endonucleases are known which represent over 250 different
specificities.[7] Over 3,000 of these have been studied in detail, and more than 800 of these are
available commercially.[8] These enzymes are routinely used for DNA modification in
laboratories, and they are a vital tool in molecular cloning.[9][10][11]

History

The term restriction enzyme originated from the studies of phage λ, a virus that infects bacteria,
and the phenomenon of host-controlled restriction and modification of such bacterial phage or
bacteriophage.[12] The phenomenon was first identified in work done in the laboratories of
Salvador Luria, Jean Weigle and Giuseppe Bertani in the early 1950s.[13][14] It was found that, for
a bacteriophage λ that can grow well in one strain of Escherichia coli, for example E. coli C, when
grown in another strain, for example E. coli K, its yields can drop significantly, by as much as 3-5
orders of magnitude. The host cell, in this example E. coli K, is known as the restricting host and
appears to have the ability to reduce the biological activity of the phage λ. If a phage becomes
established in one strain, the ability of that phage to grow also becomes restricted in other
strains. In the 1960s, it was shown in work done in the laboratories of Werner Arber and
Matthew Meselson that the restriction is caused by an enzymatic cleavage of the phage DNA,
and the enzyme involved was therefore termed a restriction enzyme.[4][15][16][17]

The restriction enzymes studied by Arber and Meselson were type I restriction enzymes, which
cleave DNA randomly away from the recognition site.[18] In 1970, Hamilton O. Smith, Thomas
Kelly and Kent Wilcox isolated and characterized the first type II restriction enzyme, HindII, from
the bacterium Haemophilus influenzae.[19][20] Restriction enzymes of this type are more useful for
laboratory work as they cleave DNA at the site of their recognition sequence and are the most
commonly used as a molecular biology tool.[21] Later, Daniel Nathans and Kathleen Danna
showed that cleavage of simian virus 40 (SV40) DNA by restriction enzymes yields specific
fragments that can be separated using polyacrylamide gel electrophoresis, thus showing that
restriction enzymes can also be used for mapping DNA.[22] For their work in the discovery and
characterization of restriction enzymes, the 1978 Nobel Prize for Physiology or Medicine was
awarded to Werner Arber, Daniel Nathans, and Hamilton O. Smith.[23] The discovery of restriction
enzymes allows DNA to be manipulated, leading to the development of recombinant DNA
technology that has many applications, for example, allowing the large scale production of
proteins such as human insulin used by diabetic patients.[13][24]

Origins

Restriction enzymes likely evolved from a common ancestor and became widespread via
horizontal gene transfer.[25][26] In addition, there is mounting evidence that restriction
endonucleases evolved as a selfish genetic element.[27]

Recognition site
A palindromic recognition site reads the same on the reverse strand as it does on the forward strand when both are read in
the same orientation

Restriction enzymes recognize a specific sequence of nucleotides[2] and produce a double-

stranded cut in the DNA. The recognition sequences can also be classified by the number of
bases in its recognition site, usually between 4 and 8 bases, and the number of bases in the
sequence will determine how often the site will appear by chance in any given genome, e.g., a 4-
base pair sequence would theoretically occur once every 4^4 or 256bp, 6 bases, 4^6 or 4,096bp,
and 8 bases would be 4^8 or 65,536bp.[28] Many of them are palindromic, meaning the base
sequence reads the same backwards and forwards.[29] In theory, there are two types of
palindromic sequences that can be possible in DNA. The mirror-like palindrome is similar to
those found in ordinary text, in which a sequence reads the same forward and backward on a
single strand of DNA, as in GTAATG. The inverted repeat palindrome is also a sequence that
reads the same forward and backward, but the forward and backward sequences are found in
complementary DNA strands (i.e., of double-stranded DNA), as in GTATAC (GTATAC being
complementary to CATATG).[30] Inverted repeat palindromes are more common and have greater
biological importance than mirror-like palindromes.

EcoRI digestion produces "sticky" ends,

whereas SmaI restriction enzyme cleavage produces "blunt" ends:

Recognition sequences in DNA differ for each restriction enzyme, producing differences in the
length, sequence and strand orientation (5' end or 3' end) of a sticky-end "overhang" of an
enzyme restriction.[31]

Different restriction enzymes that recognize the same sequence are known as neoschizomers.
These often cleave in different locales of the sequence. Different enzymes that recognize and
cleave in the same location are known as isoschizomers.

Types
Naturally occurring restriction endonucleases are categorized into four groups (Types I, II III, and
IV) based on their composition and enzyme cofactor requirements, the nature of their target
sequence, and the position of their DNA cleavage site relative to the target sequence.[32][33][34]
DNA sequence analyses of restriction enzymes however show great variations, indicating that
there are more than four types.[35] All types of enzymes recognize specific short DNA sequences
and carry out the endonucleolytic cleavage of DNA to give specific fragments with terminal 5'-
phosphates. They differ in their recognition sequence, subunit composition, cleavage position,
and cofactor requirements,[36][37] as summarised below:

Type I enzymes (EC 3.1.21.3 (https://enzyme.expasy.org/EC/3.1.21.3) ) cleave at sites

remote from a recognition site; require both ATP and S-adenosyl-L-methionine to function;
multifunctional protein with both restriction digestion and methylase (EC 2.1.1.72 (https://enz
yme.expasy.org/EC/2.1.1.72) ) activities.

Type II enzymes (EC 3.1.21.4 (https://enzyme.expasy.org/EC/3.1.21.4) ) cleave within or at

short specific distances from a recognition site; most require magnesium; single function
(restriction digestion) enzymes independent of methylase.

Type III enzymes (EC 3.1.21.5 (https://enzyme.expasy.org/EC/3.1.21.5) ) cleave at sites a

short distance from a recognition site; require ATP (but do not hydrolyse it); S-adenosyl-L-
methionine stimulates the reaction but is not required; exist as part of a complex with a
modification methylase (EC 2.1.1.72 (https://enzyme.expasy.org/EC/2.1.1.72) ).

Type IV enzymes target modified DNA, e.g. methylated, hydroxymethylated and glucosyl-
hydroxymethylated DNA

Type V enzymes utilize guide RNAs (gRNAs)

Type l

Type I restriction enzymes were the first to be identified and were first identified in two different
strains (K-12 and B) of E. coli.[38] These enzymes cut at a site that differs, and is a random
distance (at least 1000 bp) away, from their recognition site. Cleavage at these random sites
follows a process of DNA translocation, which shows that these enzymes are also molecular
motors. The recognition site is asymmetrical and is composed of two specific portions—one
containing 3–4 nucleotides, and another containing 4–5 nucleotides—separated by a non-
specific spacer of about 6–8 nucleotides. These enzymes are multifunctional and are capable of
both restriction digestion and modification activities, depending upon the methylation status of
the target DNA. The cofactors S-Adenosyl methionine (AdoMet), hydrolyzed adenosine
triphosphate (ATP), and magnesium (Mg2+) ions, are required for their full activity. Type I
restriction enzymes possess three subunits called HsdR, HsdM, and HsdS; HsdR is required for
restriction digestion; HsdM is necessary for adding methyl groups to host DNA
(methyltransferase activity), and HsdS is important for specificity of the recognition (DNA-
binding) site in addition to both restriction digestion (DNA cleavage) and modification (DNA
methyltransferase) activity.[32][38]

Type II

Type II site-specific deoxyribonuclease-like

Structure of the homodimeric restriction enzyme EcoRI (cyan and green cartoon diagram) bound to
double stranded DNA (brown tubes).[39] Two catalytic magnesium ions (one from each monomer) are
shown as magenta spheres and are adjacent to the cleaved sites in the DNA made by the enzyme
(depicted as gaps in the DNA backbone).

Identifiers

Symbol Restrct_endonuc-II-like

Pfam clan CL0236 (http://pfam.xfam.org/clan/CL0236)

InterPro IPR011335 (https://www.ebi.ac.uk/interpro/entry/

IPR011335)

SCOP2 1wte (http://scop2.mrc-lmb.cam.ac.uk/search?t=t

xt;q=1wte) / SCOPe (https://scop.berkeley.edu/
pdb/code=1wte) / SUPFAM (http://supfam.org/
SUPERFAMILY/cgi-bin/search.cgi?search_field=
1wte)

Typical type II restriction enzymes differ from type I restriction enzymes in several ways. They
form homodimers, with recognition sites that are usually undivided and palindromic and 4–8
nucleotides in length. They recognize and cleave DNA at the same site, and they do not use ATP
or AdoMet for their activity—they usually require only Mg2+ as a cofactor.[29] These enzymes
cleave the phosphodiester bond of double helix DNA. It can either cleave at the center of both
strands to yield a blunt end, or at a staggered position leaving overhangs called sticky ends.[40]
These are the most commonly available and used restriction enzymes. In the 1990s and early
2000s, new enzymes from this family were discovered that did not follow all the classical criteria
of this enzyme class, and new subfamily nomenclature was developed to divide this large family
into subcategories based on deviations from typical characteristics of type II enzymes.[29] These
subgroups are defined using a letter suffix.

Type IIB restriction enzymes (e.g., BcgI and BplI) are multimers, containing more than one
subunit.[29] They cleave DNA on both sides of their recognition to cut out the recognition site.
They require both AdoMet and Mg2+ cofactors. Type IIE restriction endonucleases (e.g., NaeI)
cleave DNA following interaction with two copies of their recognition sequence.[29] One
recognition site acts as the target for cleavage, while the other acts as an allosteric effector that
speeds up or improves the efficiency of enzyme cleavage. Similar to type IIE enzymes, type IIF
restriction endonucleases (e.g. NgoMIV) interact with two copies of their recognition sequence
but cleave both sequences at the same time.[29] Type IIG restriction endonucleases (e.g.,
RM.Eco57I) do have a single subunit, like classical Type II restriction enzymes, but require the
cofactor AdoMet to be active.[29] Type IIM restriction endonucleases, such as DpnI, are able to
recognize and cut methylated DNA.[29][41][42] Type IIS restriction endonucleases (e.g., FokI)
cleave DNA at a defined distance from their non-palindromic asymmetric recognition sites;[29]
this characteristic is widely used to perform in-vitro cloning techniques such as Golden Gate
cloning. These enzymes may function as dimers. Similarly, Type IIT restriction enzymes (e.g.,
Bpu10I and BslI) are composed of two different subunits. Some recognize palindromic
sequences while others have asymmetric recognition sites.[29]

Type III

Type III restriction enzymes (e.g., EcoP15) recognize two separate non-palindromic sequences
that are inversely oriented. They cut DNA about 20–30 base pairs after the recognition site.[43]
These enzymes contain more than one subunit and require AdoMet and ATP cofactors for their
roles in DNA methylation and restriction digestion, respectively.[44] They are components of
prokaryotic DNA restriction-modification mechanisms that protect the organism against
invading foreign DNA. Type III enzymes are hetero-oligomeric, multifunctional proteins
composed of two subunits, Res (P08764 (https://www.uniprot.org/uniprot/P08764) ) and Mod
(P08763 (https://www.uniprot.org/uniprot/P08763) ). The Mod subunit recognises the DNA
sequence specific for the system and is a modification methyltransferase; as such, it is
functionally equivalent to the M and S subunits of type I restriction endonuclease. Res is
required for restriction digestion, although it has no enzymatic activity on its own. Type III
enzymes recognise short 5–6 bp-long asymmetric DNA sequences and cleave 25–27 bp
downstream to leave short, single-stranded 5' protrusions. They require the presence of two
inversely oriented unmethylated recognition sites for restriction digestion to occur. These
enzymes methylate only one strand of the DNA, at the N-6 position of adenosyl residues, so
newly replicated DNA will have only one strand methylated, which is sufficient to protect against
restriction digestion. Type III enzymes belong to the beta-subfamily of N6 adenine
methyltransferases, containing the nine motifs that characterise this family, including motif I, the
AdoMet binding pocket (FXGXG), and motif IV, the catalytic region (S/D/N (PP) Y/F).[36][45]

Type IV

Type IV enzymes recognize modified, typically methylated DNA and are exemplified by
the McrBC and Mrr systems of E. coli.[35]

Type V

Type V restriction enzymes (e.g., the cas9-gRNA complex from CRISPRs[46]) utilize guide RNAs
to target specific non-palindromic sequences found on invading organisms. They can cut DNA of
variable length, provided that a suitable guide RNA is provided. The flexibility and ease of use of
these enzymes make them promising for future genetic engineering applications.[46][47]

Artificial restriction enzymes

Artificial restriction enzymes can be generated by fusing a natural or engineered DNA-binding

domain to a nuclease domain (often the cleavage domain of the type IIS restriction enzyme
FokI).[48] Such artificial restriction enzymes can target large DNA sites (up to 36 bp) and can be
engineered to bind to desired DNA sequences.[49] Zinc finger nucleases are the most commonly
used artificial restriction enzymes and are generally used in genetic engineering
applications,[50][51][52][53] but can also be used for more standard gene cloning applications.[54]
Other artificial restriction enzymes are based on the DNA binding domain of TAL effectors.[55][56]

In 2013, a new technology CRISPR-Cas9, based on a prokaryotic viral defense system, was
engineered for editing the genome, and it was quickly adopted in laboratories.[57] For more detail,
read CRISPR (Clustered regularly interspaced short palindromic repeats).
In 2017, a group from University of Illinois reported using an Argonaute protein taken from
Pyrococcus furiosus (PfAgo) along with guide DNA to edit DNA in vitro as artificial restriction
enzymes.[58]

Artificial ribonucleases that act as restriction enzymes for RNA have also been developed. A
PNA-based system, called a PNAzyme, has a Cu(II)-2,9-dimethylphenanthroline group that
mimics ribonucleases for specific RNA sequence and cleaves at a non-base-paired region (RNA
bulge) of the targeted RNA formed when the enzyme binds the RNA. This enzyme shows
selectivity by cleaving only at one site that either does not have a mismatch or is kinetically
preferred out of two possible cleavage sites.[59]

Nomenclature

Derivation of the EcoRI name

Abbreviation Meaning Description

E Escherichia genus

co coli specific species

R RY13 strain

order of identification

I First identified
in the bacterium

Since their discovery in the 1970s, many restriction enzymes have been identified; for example,
more than 3500 different Type II restriction enzymes have been characterized.[60] Each enzyme
is named after the bacterium from which it was isolated, using a naming system based on
bacterial genus, species and strain.[61][62] For example, the name of the EcoRI restriction enzyme
was derived as shown in the box.

Applications

Isolated restriction enzymes are used to manipulate DNA for different scientific applications.

They are used to assist insertion of genes into plasmid vectors during gene cloning and protein
production experiments. For optimal use, plasmids that are commonly used for gene cloning are
modified to include a short polylinker sequence (called the multiple cloning site, or MCS) rich in
restriction enzyme recognition sequences. This allows flexibility when inserting gene fragments
into the plasmid vector; restriction sites contained naturally within genes influence the choice of
endonuclease for digesting the DNA, since it is necessary to avoid restriction of wanted DNA
while intentionally cutting the ends of the DNA. To clone a gene fragment into a vector, both
plasmid DNA and gene insert are typically cut with the same restriction enzymes, and then glued
together with the assistance of an enzyme known as a DNA ligase.[63][64]

Restriction enzymes can also be used to distinguish gene alleles by specifically recognizing
single base changes in DNA known as single-nucleotide polymorphisms (SNPs).[65][66] This is
however only possible if a SNP alters the restriction site present in the allele. In this method, the
restriction enzyme can be used to genotype a DNA sample without the need for expensive gene
sequencing. The sample is first digested with the restriction enzyme to generate DNA fragments,
and then the different sized fragments separated by gel electrophoresis. In general, alleles with
correct restriction sites will generate two visible bands of DNA on the gel, and those with altered
restriction sites will not be cut and will generate only a single band. A DNA map by restriction
digest can also be generated that can give the relative positions of the genes.[67] The different
lengths of DNA generated by restriction digest also produce a specific pattern of bands after gel
electrophoresis, and can be used for DNA fingerprinting.

In a similar manner, restriction enzymes are used to digest genomic DNA for gene analysis by
Southern blot. This technique allows researchers to identify how many copies (or paralogues) of
a gene are present in the genome of one individual, or how many gene mutations
(polymorphisms) have occurred within a population. The latter example is called restriction
fragment length polymorphism (RFLP).[68]

Artificial restriction enzymes created by linking the FokI DNA cleavage domain with an array of
DNA binding proteins or zinc finger arrays, denoted zinc finger nucleases (ZFN), are a powerful
tool for host genome editing due to their enhanced sequence specificity. ZFN work in pairs, their
dimerization being mediated in-situ through the FokI domain. Each zinc finger array (ZFA) is
capable of recognizing 9–12 base pairs, making for 18–24 for the pair. A 5–7 bp spacer
between the cleavage sites further enhances the specificity of ZFN, making them a safe and
more precise tool that can be applied in humans. A recent Phase I clinical trial of ZFN for the
targeted abolition of the CCR5 co-receptor for HIV-1 has been undertaken.[69]

Others have proposed using the bacteria R-M system as a model for devising human anti-viral
gene or genomic vaccines and therapies since the RM system serves an innate defense-role in
bacteria by restricting tropism by bacteriophages.[70] There is research on REases and ZFN that
can cleave the DNA of various human viruses, including HSV-2, high-risk HPVs and HIV-1, with
the ultimate goal of inducing target mutagenesis and aberrations of human-infecting
viruses.[71][72][73] The human genome already contains remnants of retroviral genomes that have
been inactivated and harnessed for self-gain. Indeed, the mechanisms for silencing active L1
genomic retroelements by the three prime repair exonuclease 1 (TREX1) and excision repair
cross complementing 1(ERCC) appear to mimic the action of RM-systems in bacteria, and the
non-homologous end-joining (NHEJ) that follows the use of ZFN without a repair template.[74][75]

Examples

Examples of restriction enzymes include:[76]

 Recognition
Enzyme Source Cut
Sequence

5'---G AATTC--
5'GAATTC
-3'

EcoRI Escherichia coli

3'CTTAAG
3'---CTTAA G--
-5'

5'--- CCWGG--
5'CCWGG -3'

EcoRII Escherichia coli

3'GGWCC 3'---GGWCC --
-5'

5'---G GATCC--
5'GGATCC
-3'

BamHI Bacillus amyloliquefaciens

3'CCTAGG
3'---CCTAG G--
-5'

5'---A AGCTT--
5'AAGCTT
-3'

HindIII Haemophilus influenzae

3'TTCGAA
3'---TTCGA A--
-5'

5'TCGA
5'---T CGA---3'

TaqI Thermus aquaticus

3'AGCT
3'---AGC T---5'

5'---GC GGCCGC--
5'GCGGCCGC
-3'

NotI Nocardia otitidis

3'CGCCGGCG
3'---CGCCGG CG--
-5'

HinFI Haemophilus influenzae

5'GANTC 5'---G ANTC---3'

3'CTNAG 3'---CTNA G---5'

 5'--- GATC--
5'GATC
-3'

Sau3AI Staphylococcus aureus

3'CTAG
3'---CTAG --
-5'

5'CAGCTG
5'---CAG CTG---3'

PvuII* Proteus vulgaris

3'GTCGAC
3'---GTC GAC---5'

5'CCCGGG
5'---CCC GGG---3'

SmaI* Serratia marcescens

3'GGGCCC
3'---GGG CCC---5'

5'GGCC
5'---GG CC---3'

HaeIII* Haemophilus aegyptius

3'CCGG
3'---CC GG---5'

5'GACGC 5'---NN NN---3'

HgaI[77] Haemophilus gallinarum

3'CTGCG 3'---NN NN---5'

5'AGCT
5'---AG CT---3'

AluI* Arthrobacter luteus

3'TCGA
3'---TC GA---5'

5'GATATC
5'---GAT ATC---3'

EcoRV* Escherichia coli

3'CTATAG
3'---CTA TAG---5'

5'---CAGCAGN25
5'CAGCAGN25NN
NN---3'
EcoP15I Escherichia coli
3'GTCGTCN25NN
3'---GTCGTCN25NN
---5'

5'GGTACC
5'---GGTAC C---3'

KpnI[78] Klebsiella pneumoniae

3'CCATGG
3'---C CATGG---5'

 5'CTGCAG
5'---CTGCA G---3'

PstI[78] Providencia stuartii

3'GACGTC
3'---G ACGTC---5'

5'GAGCTC
5'---GAGCT C---3'

SacI[78] Streptomyces achromogenes

3'CTCGAG
3'---C TCGAG---5'

5'GTCGAC
5'---G TCGAC---3'

SalI[78] Streptomyces albus

3'CAGCTG
3'---CAGCT G---5'

5'AGTACT
5'---AGT ACT---3'

ScaI*[78] Streptomyces caespitosus

3'TCATGA
3'---TCA TGA---5'

5'ACTAGT
5'---A CTAGT---3'

SpeI Sphaerotilus natans

3'TGATCA
3'---TGATC A---5'

Streptomyces 5'GCATGC
5'---GCATG C---3'

SphI[78]
phaeochromogenes 3'CGTACG
3'---C GTACG---5'

5'AGGCCT
5'---AGG CCT---3'

StuI*[79][80] Streptomyces tubercidicus

3'TCCGGA
3'---TCC GGA---5'

5'TCTAGA
5'---T CTAGA---3'

XbaI[78] Xanthomonas badrii

3'AGATCT
3'---AGATC T---5'

Key:

* = blunt ends

N = C or G or T or A

W = A or T

See also
BglII – a restriction enzyme

EcoRI – a restriction enzyme

HindIII – a restriction enzyme

Homing endonuclease

List of homing endonuclease cutting sites

List of restriction enzyme cutting sites

Molecular-weight size marker

REBASE (database)

Star activity

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External links

DNA Restriction Enzymes (https://meshb.nlm.nih.gov/record/ui?name=DNA%20Restriction%2

0Enzymes) at the US National Library of Medicine Medical Subject Headings (MeSH)

Firman K (2007-11-24). "Type I Restriction-Modification" (https://web.archive.org/web/200807

06085746/http://www.typei-rm.info/) . University of Portsmouth. Archived from the original
(http://www.typei-rm.info) on 2008-07-06. Retrieved 2008-06-06.
 Goodsell DS (2000-08-01). "Restriction Enzymes" (https://web.archive.org/web/20080531095
339/http://www.rcsb.org/pdb/static.do?p=education_discussion%2Fmolecule_of_the_mont
h%2Fpdb8_1.html) . Molecule of the Month. RCSB Protein Data Bank. Archived from the
original (http://www.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_mont
h/pdb8_1.html) on 2008-05-31. Retrieved 2008-06-06.

Simmer M, Secko D (2003-08-01). "Restriction Endonucleases: Molecular Scissors for

Specifically Cutting DNA" (http://www.scq.ubc.ca/?p=249) . The Science Creative Quarterly.
Retrieved 2008-06-06.

Roberts RJ, Vincze T, Posfai, J, Macelis D. "REBASE" (https://web.archive.org/web/201502160

92957/http://rebase.neb.com/) . Archived from the original (http://rebase.neb.com) on
2015-02-16. Retrieved 2008-06-06. "Restriction Enzyme Database"

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