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, separatin ...

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

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 ''Escher ...

'' that has been shown to be important in genome maintenance. They function through catalyzing the reaction ATP + H₂O → ADP + 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 + H₂O → 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 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 The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...

– 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 Werner syndrome (WS) or Werner's syndrome, also known as "adult progeria",James, William; Berger, Timothy; Elston, Dirk (2005). ''Andrews' Diseases of the Skin: Clinical Dermatology''. (10th ed.). Saunders. . is a rare, autosomal recessive disorder ...

(WS), ''BLM'' gene in

Bloom syndrome Bloom syndrome (often abbreviated as BS in literature) is a rare autosomal recessive genetic disorder characterized by short stature, predisposition to the development of cancer, and genomic instability. BS is caused by mutations in the ''BLM'' gen ...

(BS), and ''

RECQL4 ATP-dependent DNA helicase Q4 is an enzyme that in humans is encoded by the ''RECQL4'' gene. Mutations in ''RECQL4'' are associated with the autosomal recessive disease Rothmund–Thomson syndrome, a disorder that has features of premature aging. ...

'' in

Rothmund–Thomson syndrome Rothmund–Thomson syndrome (RTS) is a rare autosomal recessive skin condition. There have been several reported cases associated with osteosarcoma. A hereditary basis, mutations in the DNA helicase ''RECQL4'' gene, causing problems during initi ...

. 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 b ...

, 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 ap ...

osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone ...

, 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 atheroma, atheromatous plaque. At onset there are usu ...

, 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, mi ...

, 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 DNA topoisomerases (or topoisomerases) are enzymes that catalyze changes in the topological state of DNA, interconverting relaxed and supercoiled forms, linked (catenated) and unlinked species, and knotted and unknotted DNA. Topological issues i ...

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

ATP-dependent

(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 the ...

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 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 repair protein XRCC4 also known as X-ray repair cross-complementing protein 4 or XRCC4 is a protein that in humans is encoded by the XRCC4 gene. In addition to humans, the XRCC4 protein is also expressed in many other metazoans, fungi and in ...

- 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 ...

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 th ...

, RAD54, RAD54B and

ATR ATR may refer to: Medicine * Acute transfusion reaction * Ataxia telangiectasia and Rad3 related, a protein involved in DNA damage repair Science and mathematics * Advanced Test Reactor, nuclear research reactor at the Idaho National Laboratory, ...

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

and

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 mainten ...

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 Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...

, 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 The DNA damage theory of aging proposes that aging is a consequence of unrepaired accumulation of naturally occurring DNA damage. Damage in this context is a DNA alteration that has an abnormal structure. Although both mitochondrial and nuclear ...

BLM helicase

Cells from humans with

are sensitive to DNA damaging agents such as UV and

methyl methanesulfonate Methyl methanesulfonate (MMS), also known as methyl mesylate, is an alkylating agent and a carcinogen. It is also a suspected reproductive toxicant, and may also be a skin/sense organ toxicant. It is used in cancer treatment. 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 dam ...

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

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 resu ...

. 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 ju ...

joint molecules, the latter being subsequently resolved as

crossovers Crossover may refer to: Entertainment Albums and songs * ''Cross Over'' (Dan Peek album) * ''Crossover'' (Dirty Rotten Imbeciles album), 1987 * ''Crossover'' (Intrigue album) * ''Crossover'' (Hitomi Shimatani album) * ''Crossover'' (Yoshino ...

. 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 a ...

'', 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) Synthesis-dependent strand annealing (SDSA) is a major mechanism of homology-directed repair of DNA double-strand breaks (DSBs). Although many of the features of SDSA were first suggested in 1976, the double-Holliday junction model proposed in 1 ...

(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 eukaryo ...

”). 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. Charle ...

RECQL4 helicase

In humans, individuals with

, and carrying the

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, mi ...

, 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 scarri ...

osteopenia Osteopenia, known as "low bone mass" or "low bone density", is a condition in which bone mineral density is low. Because their bones are weaker, people with osteopenia may have a higher risk of fractures, and some people may go on to develop osteop ...

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

. RECQL4 mutant mice also show features of accelerated aging. RECQL4 has a crucial role in

DNA end resection DNA end resection, also called 5′–3′ degradation, is a biochemical process where the blunt end of a section of double-stranded DNA (dsDNA) is modified by cutting away some nucleotides from the 5' end to produce a 3' single-stranded sequence ...

that is the initial step required for

(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

including

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

. The association of deficient RECQL4 mediated DNA repair with accelerated aging is consistent with the

References

External links

RecQ Helicases
, introduction at UNC'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