RecQ helicase is a family of
helicase
Helicases are a class of enzymes thought to be vital to all organisms. Their main function is to unpack an organism's genetic material. Helicases are motor proteins that move directionally along a nucleic acid phosphodiester backbone, separat ...
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
s initially found in ''
Escherichia coli
''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus '' Esc ...
''
that has been shown to be important in genome maintenance.
They function through catalyzing the reaction
ATP
ATP may refer to:
Companies and organizations
* Association of Tennis Professionals, men's professional tennis governing body
* American Technical Publishers, employee-owned publishing company
* ', a Danish pension
* Armenia Tree Project, non ...
+ H
2O →
ADP
Adp or ADP may refer to:
Aviation
* Aéroports de Paris, airport authority for the Parisian region in France
* Aeropuertos del Perú, airport operator for airports in northern Peru
* SLAF Anuradhapura, an airport in Sri Lanka
* Ampara Air ...
+
P and thus driving the unwinding of paired DNA and translocating in the 3' to 5' direction. These enzymes can also drive the reaction
NTP + H
2O → NDP + P to drive the unwinding of either
DNA or
RNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
.
Function
In prokaryotes RecQ is necessary for plasmid
recombination and DNA repair from UV-light, free radicals, and alkylating agents. This protein can also reverse damage from replication errors. In eukaryotes,
replication
Replication may refer to:
Science
* Replication (scientific method), one of the main principles of the scientific method, a.k.a. reproducibility
** Replication (statistics), the repetition of a test or complete experiment
** Replication crisi ...
does not proceed normally in the absence of RecQ proteins, which also function in aging, silencing, recombination and DNA repair.
Structure
RecQ family members share three regions of conserved protein sequence referred to as the:
*
N-terminal – Helicase
* middle – RecQ-conserved (RecQ-Ct) and
*
C-terminal
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
– Helicase-and-RNase-D C-terminal (HRDC) domains.
The removal of the N-terminal residues (Helicase and, RecQ-Ct domains) impairs both helicase and ATPase activity but has no effect on the binding ability of RecQ implying that the N-terminus functions as the catalytic end. Truncations of the C-terminus (HRDC domain) compromise the binding ability of RecQ but not the catalytic function. The importance of RecQ in cellular functions is exemplified by human diseases, which all lead to genomic instability and a predisposition to cancer.
Clinical significance
There are at least five human RecQ genes; and mutations in three human RecQ genes are implicated in heritable human diseases:
''WRN'' gene in
Werner syndrome (WS),
''BLM'' gene in
Bloom syndrome (BS), and ''
RECQL4'' in
Rothmund–Thomson syndrome.
These syndromes are characterized by premature aging, and can give rise to the diseases of
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bl ...
, type 2
diabetes
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level (hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...
,
osteoporosis, and
atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually ...
, which are commonly found in old age. These diseases are associated with high incidence of chromosomal abnormalities, including chromosome breaks, complex rearrangements, deletions and translocations, site specific
mutations
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosi ...
, and in particular sister chromatid exchanges (more common in BS) that are believed to be caused by a high level of somatic recombination.
Mechanism
The proper function of RecQ helicases requires the specific interaction with
topoisomerase III (Top 3). Top 3 changes the topological status of DNA by binding and cleaving single stranded DNA and passing either a single stranded or a double stranded DNA segment through the transient break and finally re-ligating the break. The interaction of RecQ helicase with topoisomerase III at the N-terminal region is involved in the suppression of spontaneous and damage induced recombination and the absence of this interaction results in a lethal or very severe phenotype. The emerging picture clearly is that RecQ helicases in concert with Top 3 are involved in maintaining genomic stability and integrity by controlling recombination events, and repairing DNA damage in the G2-phase of the cell cycle. The importance of RecQ for genomic integrity is exemplified by the diseases that arise as a consequence of mutations or malfunctions in RecQ helicases; thus it is crucial that RecQ is present and functional to ensure proper human growth and development.
WRN helicase
The
Werner syndrome ATP-dependent
helicase
Helicases are a class of enzymes thought to be vital to all organisms. Their main function is to unpack an organism's genetic material. Helicases are motor proteins that move directionally along a nucleic acid phosphodiester backbone, separat ...
(WRN helicase) is unusual among RecQ DNA family helicases in having an additional
exonuclease
Exonucleases are enzymes that work by cleaving nucleotides one at a time from the end (exo) of a polynucleotide chain. A hydrolyzing reaction that breaks phosphodiester bonds at either the 3′ or the 5′ end occurs. Its close relative is t ...
activity. WRN interacts with
DNA-PKcs
DNA-dependent protein kinase, catalytic subunit, also known as DNA-PKcs, is an enzyme that in humans is encoded by the gene designated as ''PRKDC'' or ''XRCC7''. DNA-PKcs belongs to the phosphatidylinositol 3-kinase-related kinase protein family. ...
and the
Ku protein
Ku is a dimeric protein complex that binds to DNA double-strand break ends and is required for the non-homologous end joining (NHEJ) pathway of DNA repair. Ku is evolutionarily conserved from bacteria to humans. The ancestral bacterial Ku i ...
complex. This observation, combined with evidence that WRN deficient cells produce extensive deletions at sites of joining of non-homologous DNA ends, suggests a role for WRN protein in the DNA repair process of
non-homologous end joining
Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. NHEJ is referred to as "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology direct ...
(NHEJ).
WRN also physically interacts with the major NHEJ factor X4L4 (
XRCC4-
DNA ligase 4 complex).
X4L4 stimulates WRN exonuclease activity that likely facilitates DNA end processing prior to final ligation by X4L4.
WRN also appears to play a role in resolving recombination intermediate structures during
homologous recombination
Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in cellular organisms but may be ...
al repair (HRR) of DNA double-strand breaks.
WRN participates in a complex with
RAD51
DNA repair protein RAD51 homolog 1 is a protein encoded by the gene ''RAD51''. The enzyme encoded by this gene is a member of the RAD51 protein family which assists in repair of DNA double strand breaks. RAD51 family members are homologous to the ...
, RAD54,
RAD54B
DNA repair and recombination protein RAD54B is a protein that in humans is encoded by the ''RAD54B'' gene.
The protein encoded by this gene belongs to the DEAD-like helicase superfamily. It shares similarity with ''Saccharomyces cerevisiae'' RAD5 ...
and
ATR proteins in carrying out the recombination step during inter-strand
DNA cross-link repair.
Evidence was presented that WRN plays a direct role in the repair of
methylation
In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These t ...
induced
DNA damage
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...
. The process likely involves the
helicase
Helicases are a class of enzymes thought to be vital to all organisms. Their main function is to unpack an organism's genetic material. Helicases are motor proteins that move directionally along a nucleic acid phosphodiester backbone, separat ...
and
exonuclease
Exonucleases are enzymes that work by cleaving nucleotides one at a time from the end (exo) of a polynucleotide chain. A hydrolyzing reaction that breaks phosphodiester bonds at either the 3′ or the 5′ end occurs. Its close relative is t ...
activities of WRN that operate together with
DNA polymerase beta
DNA polymerase beta, also known as POLB, is an enzyme present in eukaryotes. In humans, it is encoded by the ''POLB'' gene.
Function
In eukaryotic cells, DNA polymerase beta (POLB) performs base excision repair (BER) required for DNA maint ...
in long patch
base excision repair
Base excision repair (BER) is a cellular mechanism, studied in the fields of biochemistry and genetics, that repairs damaged DNA throughout the cell cycle. It is responsible primarily for removing small, non-helix-distorting base lesions from t ...
.
WRN was found to have a specific role in preventing or repairing DNA damages resulting from chronic
oxidative stress
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal re ...
, particularly in slowly replicating cells.
This finding suggested that WRN may be important in dealing with oxidative DNA damages that underlie normal aging
(see
DNA damage theory of aging).
BLM helicase
Cells from humans with
Bloom syndrome are sensitive to DNA damaging agents such as
UV and
methyl methanesulfonate indicating deficient
DNA repair
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...
capability.
The budding yeast ''
Saccharomyces cerevisiae
''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have been o ...
'' encodes an ortholog of the Bloom syndrome (BLM) protein that is designated
Sgs1
Sgs1, also known as slow growth suppressor 1, is a DNA helicase protein found in ''Saccharomyces cerevisiae''. It is a homolog of the bacterial RecQ helicase. Like the other members of the RecQ helicase family, Sgs1 is important for DNA repair ...
(Small growth suppressor 1). Sgs1(BLM) is a helicase that functions in
homologous recombination
Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in cellular organisms but may be ...
al repair of DNA double-strand breaks. The Sgs1(BLM) helicase appears to be a central regulator of most of the recombination events that occur during ''S. cerevisiae''
meiosis
Meiosis (; , since it is a reductional division) is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately ...
.
During normal meiosis Sgs1(BLM) is responsible for directing recombination towards the alternate formation of either early non-crossovers or
Holliday junction
A Holliday junction is a branched nucleic acid structure that contains four double-stranded arms joined. These arms may adopt one of several conformations depending on buffer salt concentrations and the sequence of nucleobases closest to the ...
joint molecules, the latter being subsequently resolved as
crossovers.
In the plant ''
Arabidopsis thaliana
''Arabidopsis thaliana'', the thale cress, mouse-ear cress or arabidopsis, is a small flowering plant native to Eurasia and Africa. ''A. thaliana'' is considered a weed; it is found along the shoulders of roads and in disturbed land.
A winter ...
'', homologs of the Sgs1(BLM) helicase act as major barriers to meiotic crossover formation.
These helicases are thought to displace the invading strand allowing its annealing with the other 3’overhang end of the double-strand break, leading to non-crossover recombinant formation by a process called
synthesis-dependent strand annealing (SDSA) (see Wikipedia article “
Genetic recombination
Genetic recombination (also known as genetic reshuffling) is the exchange of genetic material between different organisms which leads to production of offspring with combinations of traits that differ from those found in either parent. In eukary ...
”). It is estimated that only about 5% of double-strand breaks are repaired by crossover recombination. Sequela-Arnaud et al.
suggested that crossover numbers are restricted because of the long-term costs of crossover recombination, that is, the breaking up of favorable genetic combinations of alleles built up by past
natural selection
Natural selection is the differential survival and reproduction of individuals due to differences in phenotype. It is a key mechanism of evolution, the change in the heritable traits characteristic of a population over generations. Cha ...
.
RECQL4 helicase
In humans, individuals with
Rothmund–Thomson syndrome, and carrying the
RECQL4 germline
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...
, have several clinical features of accelerated
aging
Ageing ( BE) or aging ( AE) is the process of becoming older. The term refers mainly to humans, many other animals, and fungi, whereas for example, bacteria, perennial plants and some simple animals are potentially biologically immortal. In ...
. These features include atrophic skin and pigment changes,
alopecia
Hair loss, also known as alopecia or baldness, refers to a loss of hair from part of the head or body. Typically at least the head is involved. The severity of hair loss can vary from a small area to the entire body. Inflammation or scarr ...
,
osteopenia,
cataract
A cataract is a cloudy area in the lens of the eye that leads to a decrease in vision. Cataracts often develop slowly and can affect one or both eyes. Symptoms may include faded colors, blurry or double vision, halos around light, trouble w ...
s and an increased incidence of
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bl ...
.
RECQL4 mutant mice also show features of accelerated aging.
RECQL4 has a crucial role in
DNA end resection that is the initial step required for
homologous recombination
Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in cellular organisms but may be ...
(HR)-dependent double-strand break repair.
When RECQL4 is depleted, HR-mediated repair and 5’ end resection are severely reduced ''in vivo''. RECQL4 also appears to be necessary for other forms of
DNA repair
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...
including
non-homologous end joining
Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. NHEJ is referred to as "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology direct ...
,
nucleotide excision repair
Nucleotide excision repair is a DNA repair mechanism. DNA damage occurs constantly because of chemicals (e.g. intercalating agents), radiation and other mutagens. Three excision repair pathways exist to repair single stranded DNA damage: Nucle ...
and
base excision repair
Base excision repair (BER) is a cellular mechanism, studied in the fields of biochemistry and genetics, that repairs damaged DNA throughout the cell cycle. It is responsible primarily for removing small, non-helix-distorting base lesions from t ...
.
The association of deficient RECQL4 mediated DNA repair with accelerated aging is consistent with the
DNA damage theory of aging.
See also
*
Bloom syndrome
References
Further reading
*
*
External links
RecQ Helicases, introduction at
UNC UNC is a three-letter abbreviation that may refer to:
Education
* University of Northern California (disambiguation), which may refer to:
** University of Northern California (Santa Rosa), in Petaluma, California, United States
** University of Nor ...
's Sekelsky Lab.
BLM gene encodes a RecQ Helicase description of the gene
{{Portal bar, Biology, border=no
EC 3.6.1
Aging-related enzymes
Senescence