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The maintenance of the stability of genetic material is an essential feature of every living organism. Organisms across all kingdoms have evolved diverse and highly efficient repair mechanisms to protect the genome from deleterious consequences of various genotoxic factors that might tend to destabilize the integrity of the genome in each generation.
One such group of proteins that is actively involved in genome surveillance is the RecQ helicase family. In humans, five RecQ helicases have been identified and three of them namely, WRN, BLM and RecQL4 have been linked to genetic diseases characterized by genome instability, premature aging and cancer predisposition.
This helicase family plays important roles in various DNA repair pathways including protecting the genome from illegitimate recombination during chromosome segregation in mitosis and assuring genome stability.
This review mainly focuses on various roles of human RecQ helicases in the process of recombination-based DNA repair to maintain genome stability and physiological consequences of their defects in the re of cancer and premature aging. The stability of the genetic leii from one generation to another is an important and essential feature for every living organism. The failure to do so efficiently can lead to chromosomal abnormalities, developmental abnormalities, progression of cancer and premature aging.
Living organisms encounter different kinds of stresses provided by genotoxic elements from within products of normal cellular metabolism i. To counteract these stress responses, organisms have evolved diverse and highly efficient DNA repair pathways. The repair proteins function in a highly coordinated fashion with other DNA metabolic processes during the different stages of the cell cycle to maintain genome integrity in each generation.
An overview of the 20099 between DNA repair, cellular llei responses, genome stability and aging has been presented in Fig. Overview of relationship between cellular stress responses, DNA repair and genome stability. During the course of their life span, organisms tolerate multiple stresses which might have deleterious effects on their genome. Efficient DNA repair machinery in an organism leads to genomic stability, and protects the genome from harmful effects of stress.
One major family of proteins that is actively lej in maintaining genome stability is the RecQ helicases.
Roles of RECQ helicases in recombination based DNA repair, genomic stability and aging
The RecQ protein is evolutionarily conserved from bacteria, yeast and 20009 to plants. There is only one RecQ homolog in Escherichia coli RecQ and yeast namely, Sgs1 and Rqh1 in Saccharomyces cerevisiae and Schizosaccharomyces pomberespectivelybut five RecQ homologs have been identified in both human and mouse. The largest number of RecQ helicases has been reported in plants, with a total of seven RecQ helicases.
Therefore, the function of RecQ helicases seems to have adapted to the complexity of genomes present in higher eukaryotes by increasing their number. The domain architecture of RecQ helicase family members from different organisms is shown in Fig. Domain architecture of RecQ helicase family. RecQ helicases from different organisms are shown. All the members have a conserved helicase domain in the central region of the protein yellow.
The nuclear localization signal depicted in red is present at the C-terminus in most of the family members, except in RECQL4 where it resides at the N-terminus. RecQ helicases play 209 roles in various DNA repair pathways including double-strand break DSB repair and protecting the genome from illegitimate recombination during chromosome segregation in mitosis Chakraverty and Hickson ; Shen and Loeb ; van Brabant et al. In higher eukaryotes, homologous recombination HR is essential for segregation of homologous chromosomes during meiosis, generation of genetic diversity and maintenance of telomeres Hoeijmakers ; West ; Krogh and Symington In addition, recombination-related processes also function in the repair of DNA double-strand breaks DSBsinterstrand cross-links ICLs 12304, and recovery of stalled or broken replication forks in DNA replication through a series of interrelated pathways Fig.
Two major recombination pathways have been identified in eukaryotes that are distinct with respect to mechanism and DNA homology requirements. Homologous recombination HR corrects strand breaks using homologous sequences primarily from the sister chromatid and, 1203 a lesser extent, from the homologous li Johnson and Jasin ; Liang et al.
Therefore, it is a high fidelity repair mechanism. These repair pathways involve many proteins whose deficiency results in genome instability, cancer predisposition and premature aging Ouyang et al. The possible roles of different RecQ helicases at the multiple steps of major recombination pathways are represented in Fig.
RecQ helicases play important roles in various DNA metabolic and repair pathways involving homologous recombination. The RecQ helicases are involved in i Resolving aberrant structures encountered at the replication fork during normal DNA replication, ii Replication restart at collapsed replication fork sites which arise due to the presence of a nick within the leading strand ahead of replication fork. When the progressing replication fork encounter these nicks which mimic double strand breaksit leads to replication arrest.
RecQ helicases helps in the replication recovery at the arrested replication fork by promoting fork regression and homologous recombination, iii Lesion bypass when the base error is present in the lagging strand. The nick is created due to removal of an incorrectly incorporated nucleotide in the lagging strand which is filled by recombination-mediated gap repair. RecQ helicases are involved in multiple steps of major recombination pathways.
The members of the RecQ helicase family interacts with various proteins involved in different steps of the major recombination pathways i.
See text for details. One of the prominent functions of RecQ helicases is to prevent aberrant and potentially recombinogenic DNA structures that arise as intermediates during DNA replication, repair, or recombination. RecQ helicases in association with other repair proteins might properly resolve such recombinogenic structures to prevent illegitimate and deleterious crossover recombination.
Various RecQ-deficient eukaryotic cells display elevated levels of recombination, suggesting their anti-recombination functions Bugreev et al. This review mainly focuses on the roles of various RecQ helicases in the process of DNA recombination to maintain the integrity of the genome during the faithful segregation and transmission from one generation to the next, and the genetic and physiological abnormalities associated with their defects.
Werner syndrome WS is an autosomal recessive disease characterized by premature aging associated with genome instability and an elevated risk of cancer. One of the earliest features recognized in primary fibroblasts cell derived from WS patients is limited replicative capacity and reduced ability to lfi. The WS fibroblasts undergo premature entry into senescence compared to normal cells, which could be one of the reasons for premature aging in WRN patients Epstein et al.
However, not all cell types derived from WS patients undergo premature senescence. Human T lymphocytes represent a well-characterized example of such a cell type.
These cells show no significant reduction in growth capacity 209 to normal controls James et al.
Roles of RECQ helicases in recombination based DNA repair, genomic stability and aging
Cytogenetic observations of WS cells show various types of chromosomal aberrations including deletions, 200, and rearrangements as well as increased spontaneous mutation Hoehn et al. Cellular studies have shown marked reduction in cell proliferation following mitotic recombination in WS fibroblasts Prince et al. These findings suggested a role of WRN in mitotic recombination. This group observed that WS fibroblast cell lines failed to resolve recombinant products.
Thus, in the absence of WRN, unresolved or disrupted gene conversion products may lead to gene rearrangement or loss mediated by other processes and result in recombination-initiated mitotic arrest, and cell death Prince et al.
Several lines of evidence suggest that WRN is actively involved in the homologous recombination pathway. A defect in this pathway consequently results in a loss or gain of genetic information. Thus, in the absence of WRN, regulatory processes controlling NHEJ may be disrupted and relatively large and potentially oncogenic deletions would be generated, leading to accelerated decline in the fidelity of DSB fe.
Further, X4L4 is able to ligate a substrate processed by WRN exonuclease, suggesting the functional importance of this interaction Kusumoto et al. Molecular studies by Cheng et al. Further, Otterlei et al.
Recently, Rodriguez-Lopez et al. Furthermore, RusA expression rescued the hypersensitivity of the WS fibroblasts cell to camptothecin and 4-NQO inducing the formation of a double-strand break and fork collapse Rodriguez-Lopez et al.
WRN also promotes the ATP-dependent translocation of Holliday junctions which are consistent with the model in which WRN prevents aberrant recombination events at sites of stalled replication forks by dissociating recombination intermediates Constantinou et al. The role of WRN in resolving steps of recombination is supported by the observation that WRN contains an enzymatic property which unwinds Holliday junction structures.
In vitro studies have demonstrated that the WRN oei activity is able to unwind HJs through a branch migration-like activity Constantinou et al. WRN also plays an important lej in the response to replication fork arrest and its recovery during the S-phase of the cell cycle.
These phenotypes account for the loss of proliferative capacity of WS cells and appear to be responsible for early onset of cellular senescence. It has been further observed that there is significant asymmetry in bidirectional replication fork in the absence of functional WRN protein which suggests that WRN might acts to prevent collapse of replication forks or to resolve DNA junctions at stalled replication fork in normal cells Rodriguez-Lopez et al.
Further, as mentioned earlier WRN deficient 2090 are hypersensitive to clastogens induces replication fork blockageDNA interstrand cross-linking agents, camptothecin, and hydroxyurea HU Okada et al. In addition, several lines of evidence support the view that WRN might play an upstream role in response to DSBs at replication forks.
Replication fork stalling or pei is dependent on whether the fork-blocking lesion is on the leading strand or lagging strand. If the polymerase is kept in the coupled replication complex and skips ahead to the next primer to synthesis a new Okazaki fragment, leaving behind a single strand gap containing the lesion, HR is the preferred gap repair pathway.
Another pathway to repair the gap is the generation of Displacement loop D-loop structures recombination intermediates by 0209 of the blocked nascent lagging strand into its sister chromatid and extension 12304 the invading strand by DNA polymerase. The extended D-loop structures are excellent substrates for WRN and BLM helicase and the dissociated D-loops would be used as a substrate for replication restart.
Further, WRN exonuclease activity enhances d of forks with smaller gaps on the leading arm. This finding suggests that WRN might regress replication forks in vivo, proposing a role for WRN in le recovery of replication arrest Machwe et al.
Increasing evidence suggests that telomeric dysfunction is likely to be an important factor for premature senescence and decreased replicative capacity observed in WS cells.
Consistent with roles of other RecQ helicases at the telomeres, human BS cells also show telomere defects Lillard-Wetherell et al. These findings suggest important roles played by RecQ helicases in telomere maintenance. It has been shown that most human somatic cells do not possess sufficient telomerase to maintain telomere length intact through successive generations and in the absence of telomerase, telomeres progressively become shortened in each generation and eventually become dysfunctional, leading to genomic instability, growth arrest, and apoptosis Harley et al.
The primary role of telomeres in the cell is to protect the ends of linear chromosomes and prevent them from being recognized as double strand breaks DSBs by the cellular damage 122034 machinery.
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Loss of telomere structure and function induces a DNA damage response that involves several proteins that normally respond to the process of DSBs de Lange Studies in yeast have shown the involvement of RecQ helicase protein in homologous recombination pathways at the telomeres.
In budding yeast, RecQ helicase Sgs1 functions in an alternative pathway for lengthening of telomeres ALT that occur via recombination in type II survivors of telomerase-negative mutants Johnson et al. Evidence for an ALT-like pathway has also been detected in telomerase-negative mammalian cells from tumors or upon SV40 transformation Yeager et al.
The precise mechanism of the ALT pathway in human cells is poorly understood, but several models have proposed the involvement of intra- and intertelomeric D-loop formation.
It has been postulated that the initiation of telomeric recombination may signal WRN recruitment to either suppress recombination or to dissociate intermediates to ensure proper separation of the recombining telomeric strand. In yeast, RecQ helicase Sgs1 acts in the resolution of recombination intermediates in telomerase deficient yeast strains near senescence, when critically shortened telomeres undergo recombination in an effort to restore telomere length Lee et al.
Failure to resolve these recombinant structures results in rapid senescence. Further data support the suggestion that Sgs1 is involved in the resolution of telomeric recombination intermediates rather than preventing its formation at the initiation stage Lee et al. These findings suggest that WRN normally suppresses sister chromatid exchanges between telomeres in the shortened or dysfunctional telomeres.
Thus, a requirement for WRN and regulation of recombination at the telomeres to suppress ALT may become more crucial as the telomeres shorten. The proteins of the NHEJ pathway of recombination, i. Ku suppresses recombination at telomeres that are made dysfunctional through the loss of telomeric protein TRF2.
Taken together, the above findings support a multidimensional role of WRN in protecting the genome from aberrations and instability.
The loss of WRN in cells leads to proliferative defects, limited replicative capacity, and premature cellular senescence. These phenotypes could be due to global genomic damage which results in the rapid exit from the cell cycle of 22009 defective cells compared to normal control cells Faragher et al.