human recq helicases in dna repair, recombination, and replication

The RecQ helicases motifs and domains are presented mainly based on the annotations by the GenomeNet Database (https://www.genome.jp/), with information from published literatures. A recent study reported that CtIP interacts with BLM and stimulates its helicase activity, further promoting DNA2/BLM-mediated extensive resection (Daley et al., 2017). German J., Sanz M. M., Ciocci S., Ye T. Z., Ellis N. A. RecQ MMEJ and SSA were initially identified in cells that were deficient in NHEJ and/or HR, and thus, both were believed to be strictly backup pathways (Fairman et al., 1992; Boulton and Jackson, 1996; Mason et al., 1996; Kabotyanski et al., 1998), but it has been found that, even in NHEJ- and HR-proficient cells, a small percentage of DSBs are repaired by these alternative pathways (Truong et al., 2013). RecQ DNA helicases are a conserved protein family found in bacteria, fungus, plants, and animals. (1996). (2011). In addition to NHEJ, WRN promotes HR-mediated DSB repair in multiple ways (Saintigny et al., 2002; Chen et al., 2003). RecQs may resolve inter- and intratelomeric substrates, G quadruplexes (G4s), and telomeric T-loops and D-loops. 2023 May 11;9(1):157. doi: 10.1038/s41420-023-01451-9. DNA binding residues in the RQC domain of Werner protein are critical for its catalytic activities. Saponaro M., Kantidakis T., Mitter R., Kelly G. P., Heron M., Williams H., et al. Taylor A. M. R., Rothblum-Oviatt C., Ellis N. A., Hickson I. D., Meyer S., Crawford T. O., et al. RECQL1 consists of 649 amino acid residues, and it possesses the conserved core helicase domain, RecQ Zn2+ binding motif, and the RQC domain (Figure 3). Division of Molecular Radiation Biology, Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX, United States, Edited by: Binfeng Lu, University of Pittsburgh, United States, Reviewed by: Sudha Sharma, Howard University, United States; Matthew Bochman, Indiana University, United States, This article was submitted to Cell Death and Survival, a section of the journal Frontiers in Cell and Developmental Biology. Interestingly, WRN actively inhibits DNA end resection by limiting the recruitment of MRE11 and CtIP to DSBs in the G1 phase of the cell cycle (Shamanna et al., 2016b). (2000). The RecQ DNA helicases in DNA Repair - PMC - National It is an accurate process as it employs DNA sequences homologous to/near the broken ends to drive repair, predominantly using the sister chromatid as a template for DSB repair rather than the homologous chromosome. Once aligned, the non-complementary sequences generate 3 ssDNA overhangs that are removed by nucleases. Keywords: Nimonkar A. V., Ozsoy A. Singh T. R., Ali A. M., Busygina V., Raynard S., Fan Q., Du C. H., et al. Croteau D. L., Rossi M. L., Canugovi C., Tian J., Sykora P., Ramamoorthy M., et al. Garcia P. L., Liu Y., Jiricny J., West S. C., Janscak P. (2004). Exploiting the microhomology-mediated end-joining pathway in cancer therapy. However, a recent study showed that RECQL5 possesses a stronger annealing activity on long or small duplexed substrates compared to the other RecQ helicases, which is not inhibited by the presence of ATP (Khadka et al., 2016). A role for RECQL1 in DSB repair was initially identified via the observation that Recql1 knockout mouse embryonic fibroblasts (MEFs) are highly sensitive to IR and that knockdown of RECQL1 in human cells results in increased cell death to IR and the topoisomerase 1 (TOP1) inhibitor camptothecin (CPT) (Sharma and Brosh Jr., 2007; Sharma et al., 2007). Enzymatic mechanism of the WRN Helicase/nuclease. Discovery of a Novel Bloom's Syndrome Protein (BLM) Inhibitor Suppressing Growth and Metastasis of Prostate Cancer. BLM functions in multiple DNA repair pathways, with its most-defined role in HR. The Blooms and Werners syndrome proteins are DNA structure-specific Helicases. RecQ helicases possess 3 to 5 directionality and can unwind a variety of DNA structures including B-form DNA, forked DNA duplexes, D-loops, DNA junctions, and G-quadruplexes (Croteau et al., 2014). BLM-DNA2-RPA-MRN and EXO1-BLM-RPA-MRN constitute two DNA end resection machineries for human DNA break repair. The human Rothmund-Thomson syndrome gene product, RECQL4, localizes to distinct nuclear foci that coincide with proteins involved in the maintenance of genome stability. The .gov means its official. CtIP promotes microhomology-mediated alternative end joining during class-switch recombination. In line with WRNs involvement in multiple DSB repair pathways, the recruitment of this RecQ helicase to DSBs occurs in the G1, S, and G2 phases of the cell cycle (Shamanna et al., 2016b). WebHelicases are classically defined as molecular motors that are able to couple nucleoside triphosphate (NTP) hydrolysis (typically of ATP) to the unwinding of polynucleic acids 1 ( A., Gerrits B., et al. Furthermore, RECQL5 deficiency causes an increased occupancy of RAD51 at DSBs and evaluated sister chromatid exchange when the Holliday junction dissolution pathway is inactivated or a high load of DNA damage is generated in the cell (Paliwal et al., 2014). Kusumoto-Matsuo R., Ghosh D., Karmakar P., May A., Ramsden D., Bohr V. A. RecQ DNA helicases are a conserved protein family found in bacteria, fungus, plants, and animals. (2001). (2003). WRN Helicase promotes repair of DNA double-strand breaks caused by aberrant mismatch repair of chromium-DNA adducts. (2015). and transmitted securely. WRN interacts with MRE11 and NBS1, which is enhanced by IR, and results in the promotion of WRN helicase activity (Cheng et al., 2004). The .gov means its official. Collectively, these and other unanswered questions drive us and others to understand the role of each RecQ helicase in DSB repair, how defects drive human disorders, and how these enzymes may be targets for therapy. Unfortunately, BS patients have a short life span (less than 30 years), and the major cause of death is cancer (Cunniff et al., 2017; de Renty and Ellis, 2017). DSBs arise from various stresses by endogenous or exogenous factors and can lead to arrest of the cell cycle, transcription, activation of the DNA damage response, and repair of the DNA damage. In this review, we will introduce the human RecQ helicase family, describe in detail their roles in DSB repair, and provide relevance between the dysfunction of RecQ helicases and human diseases. (2020). WebAbstract RecQ helicases are an important family of genome surveillance proteins conserved from bacteria to humans. Rogers C. M., Wang J. C., Noguchi H., Imasaki T., Takagi Y., Bochman M. L. (2017). 2008 Nov 1;7(11):1776-86. doi: 10.1016/j.dnarep.2008.07.017. DNA-dependent protein kinase promotes DNA end processing by MRN and CtIP. Mutations in RECQL4 are associated with three genetic disorders, RothmundThomson syndrome (RTS), BallerGerold syndrome (BGS), and RAPADILINO syndrome. Bugreev D. V., Yu X., Egelman E. H., Mazin A. V. (2007). Chen L., Huang S., Lee L., Davalos A., Schiestl R. H., Campisi J., et al. Human RecQ Helicases in DNA Double-Strand Break Repair Human RecQ5beta, a large isomer of RecQ5 DNA Helicase, localizes in the nucleoplasm and interacts with topoisomerases 3alpha and 3beta. De novo myelodysplastic syndrome in a Rothmund-Thomson Syndrome patient with novel pathogenic. An official website of the United States government. Davis A. J., Chen B. P., Chen D. J. See this image and copyright information in PMC. A recent study reported that these two Ku-binding motifs of WRN function cooperatively to bind the Ku heterodimer and that the N-terminal Ku-binding motif mediates Ku-dependent stimulation of WRN exonuclease activity, promoting DSB repair (Grundy et al., 2016). (2016). Popuri V., Hsu J., Khadka P., Horvath K., Liu Y., Croteau D. L., et al. Mutations in RECQL4 are associated with three rare autosomal-recessive disorders: RothmundThomson syndrome (RTS; OMIM #268400), RAPADILINO (RAPA; OMIM #266280), and BallerGerold syndrome (BGS; OMIM #218600) (Siitonen et al., 2009; Larizza et al., 2010, 2013). Inactivating mutations in 3 of the 5 human RecQ helicases are responsible for the pathogenesis of Werner syndrome (WS), Bloom syndrome (BS), Rothmund-Thomson syndrome (RTS), RAPADILINO, and Baller-Gerold syndrome (BGS). (1974). DNA-PKcs promotes chromatin decondensation to facilitate initiation of the DNA damage response. DNA helicases involved in DNA repair and their roles in cancer 2009 Jun;10(3):235-52. doi: 10.1007/s10522-008-9205-z. Accumulation of Werner protein at DNA double-strand breaks in human cells. Proteome-wide identification of WRN-interacting proteins in untreated and nuclease-treated samples. NHEJ is a flexible process that directs re-ligation of the broken DNA molecule in a template-independent manner and is active in all phases of the cell cycle (Davis et al., 2014; Pannunzio et al., 2018). Bloom syndrome protein plays a multifaceted role in HR as it is required for the early phase of the pathway (DNA end resection) as well as one of the terminal steps (dissolution of Holliday junctions) (Croteau et al., 2014). -, Aoude L. G., Bonazzi V. F., Brosda S., Patel K., Koufariotis L. T., Oey H., et al. Moreover, BRCA1 also directly interacts with WRN and stimulates both the helicase and exonuclease activities of WRN, which likely promotes DNA end resection (Cheng et al., 2006). (2011). (2013). A functional interaction of Ku with Werner exonuclease facilitates digestion of damaged DNA. (2015). HR is initiated by the MRE11/RAD50/NBS1 (MRN) complex in conjunction with CtIP via the endonuclease and 35 exonuclease activities of MRE11 (Lengsfeld et al., 2007; Sartori et al., 2007; Garcia et al., 2011; Cannavo and Cejka, 2014; Deshpande et al., 2020). Among these questions, investigating the posttranslational modifications of RecQ helicases may shed light on many unknown mechanisms, including the enzymatic roles of RecQ helicases in specific steps of DSB repair pathways, coordination between the RecQ helicases during specific repair processes, and the role(s) of RecQ helicases in DSB repair pathway choice. RECQL5 has unique strand annealing properties relative to the other human RecQ Helicase proteins. ML216 Prevents DNA Damage-Induced Senescence by Modulating DBC1-BLM Interaction. RECQL5/Recql5 Helicase regulates homologous recombination and suppresses tumor formation via disruption of Rad51 presynaptic filaments. (2019). DNA double-strand break repair-pathway choice in somatic mammalian cells. DSS1 is required for RAD51 focus formation and genomic stability in mammalian cells. The structural and functional characterization of human RecQ4 reveals insights into its Helicase mechanism. In addition, RECQL1 forms a complex with RAD51 (Sharma and Brosh Jr., 2007) and promotes the processing of Holliday junctions by promoting branch migration (LeRoy et al., 2005; Mazina et al., 2012), indicating that RECQL1 functions in resolving HR intermediates. DNA damage response factors from diverse pathways, including DNA crosslink repair, mediate alternative end joining. No use, distribution or reproduction is permitted which does not comply with these terms. An essential role for CtIP in chromosomal translocation formation through an alternative end-joining pathway. Yeast Hrq1 shares structural and functional homology with the disease-linked human RecQ4 Helicase. Function of recQ family helicase in genome stability. RECQL4 preferably interacts with Ku70 to promote NHEJ in G1 when the overall CDK activity is low. Sae2, Exo1 and Sgs1 collaborate in DNA double-strand break processing. Putative roles of RecQ helicases during initiation of, RecQ helicases (BLM, WRN, and RECQL4) in telomere maintenance and repair. Werner syndrome helicase (WRN) is encoded by the WRN gene, which is located at chromosome 8p11-12 (Goto et al., 1992; Yu et al., 1996; Goto et al., 1997). The RecQ DNA Helicases in DNA Repair | Annual Review of Genetics The helicase activity of WRN is stimulated by a number of proteins, including RPA, the Ku heterodimer, MRN complex, and the telomere protein TRF2 (Cheng et al., 2004; Sommers et al., 2005; BroshJr., Opresko and Bohr, 2006). Such an action is essential for the Multiple genetically independent pathways have evolved that mediate the repair of DNA double-strand break (DSB), and RecQ helicases play pivotal roles in each of them. DSBs arise from various stresses by endogenous or exogenous factors and can lead to arrest of the cell cycle, transcription, activation of the DNA damage response, and repair of the DNA damage. BLM participates in different pathways required for DNA metabolism, which it achieves by interacting with many proteins via either its N-terminal domain or undefined C-terminal region (Croteau et al., 2014). Unable to load your collection due to an error, Unable to load your delegates due to an error. Hotspots for initiation of meiotic recombination. RecQ helicases are proposed to function at the interface between DNA replication and recombination to 'repair' damaged replication forks. Cooper M. P., Machwe A., Orren D. K., Brosh R. M., Ramsden D., Bohr V. A. Scully R., Panday A., Elango R., Willis N. A. RecQ helicase-interacting proteins in DSB repair pathways. Causes and consequences of DNA double-strand breaks (DSBs). Blooms syndrome: why not premature aging? RMI, a new OB-fold complex essential for Bloom syndrome protein to maintain genome stability. RECQ1 Helicase in genomic stability and cancer. Chen Y., Dui W., Yu Z., Li C., Ma J., Jiao R. (2010). RecQ helicase Meningioma associated with Werner syndromecase report. Yu C. E., Oshima J., Fu Y. H., Wijsman E. M., Hisama F., Alisch R., et al. Hrq1 functions independently of Sgs1 to preserve genome integrity in. (2012a). Functional conservation of RecQ helicase BLM between humans and Drosophila melanogaster. Choi D. H., Lee R., Kwon S. H., Bae S. H. (2013). Using a GFP-based reporter assay, depletion of BLM by siRNA reduces SSA in HEK293 cells, but not in U2OS cells (Sturzenegger et al., 2014). Werner syndrome (WRN) gene variants and their association with altered function and age-associated diseases. National Library of Medicine Human Recently, WRN was identified as a synthetic lethal vulnerability in cancers with microsatellite instability (Chan et al., 2019; van Wietmarschen et al., 2020). Acta 1813 473479. 2022 Dec 29;12(1):145. doi: 10.3390/cells12010145. Interestingly, a recent study showed that the binding of multiple RPAs super boosts the unwinding activity of WRN so that this helicase can unidirectionally unwind a duplex with a size of >1 kb (Lee et al., 2018). (1998). During SSA, the generated 3 ssDNAs are annealed by RAD52 via alignment of homologous sequences, whereas multiple enzymes are responsive for end bridging and annealing in MMEJ, including the MRN complex, PARP1, and Pol (Sallmyr and Tomkinson, 2018). WebHelicases are ubiquitous enzymes that play critical roles in DNA replication, recombination, repair, and transcription. Unique and important consequences of RECQ1 deficiency in mammalian cells. A role for RECQL4 in NHEJ was first indicated when it was found that RECQL4 binds to restriction enzyme-generated DSBs near the Ku70-binding site and that RECQL4 is required for the repair of these DSBs in Xenopus extracts (Kumata et al., 2007). Pathogenic germline variants are associated with poor survival in stage III/IV melanoma patients. RECQL1, similar to RAD51, protects stalled replication forks from MRE11-dependent degradation (Berti et al., 2013; Mason et al., 2019), suggesting that RECQL1 may play an indirect role in the protection and/or repair of one-ended DSBs at replication forks and is not directly required for strand invasion or homology search in HR at two-ended DSBs. The RecQ Helicase Family Is Conserved from Bacteria to Humans To maintain genome integrity, RecQ-like DNA helicases act as key factors in homologous recombination (HR) and recombinational DNA repair and, in some organisms, perform accessory roles in DNA replication and transcription. Abbreviations: BIR, break-induced replication; HJ, Holliday junction; RPA, replication protein A; RQ4, RECQL4; TIN2, TRF1-interacting nuclear factor 2; TPP1, POT1-interacting telomere endbinding protein. Fewings E., Larionov A., Redman J., Goldgraben M. A., Scarth J., Richardson S., et al. Li M., Liu B., Yi J., Yang Y., Wang J., Zhu W. G., et al. The average life span of WS patients is 54 years, and the major death causes of WS patients are cancer and myocardial infarction (Huang et al., 2006; Goto et al., 2013; Oshima et al., 2017). Shamanna R. A., Lu H., Croteau D. L., Arora A., Agarwal D., Ball G., et al. Humans have five RecQ helicases: RECQL1, Bloom syndrome protein (BLM), Werner syndrome helicase (WRN), RECQL4, and RECQL5. Lan L., Nakajima S., Komatsu K., Nussenzweig A., Shimamoto A., Oshima J., et al. The site is secure. (1995). Human RecQ Helicases in DNA Repair, Recombination, -, Ammazzalorso F., Pirzio L. M., Bignami M., Franchitto A., Pichierri P. (2010). Matsumoto T., Shimamoto A., Goto M., Furuichi Y. (2012). Constantinou A., Tarsounas M., Karow J. K., Brosh R. M., Bohr V. A., Hickson I. D., et al. Patterson-Fortin J., DAndrea A. D. (2020). (2009). Another report indicates that WRN is involved in NHEJ indirectly by upregulating the transcription level of the key NHEJ factor XLF (Liu et al., 2014). 2023 Feb 20;5(2):125-130. doi: 10.1097/BS9.0000000000000152. Furthermore, the helicase activity of RECQL4 promotes DNA end processing and HR, and this process is regulated by CDK1/2-mediated phosphorylation (Lu et al., 2017). The C-terminal region of WRN may be required for SSA (Muftuoglu et al., 2008). (2013). Potential role for the BLM Helicase in recombinational repair via a conserved interaction with RAD51. Wu L., Chan K. L., Ralf C., Bernstein D. A., Garcia P. L., Bohr V. A., et al. If the ends of the DSB are not compatible for ligation, different enzymes are required, including those that resect DNA ends, fill in gaps, or remove blocking end groups, to process the DNA ends to allow ligation (Pannunzio et al., 2018). Clinical utility gene card for: Rothmund-Thomson syndrome. All three isoforms have the core helicase domain, while only RECQL5 has helicase activity in vitro (Shimamoto et al., 2000). eCollection 2023 Apr. Human RecQ Helicases in DNA repair, recombination, and replication. (1992). 2021;161(6-7):305-327. doi: 10.1159/000516568. (2017). Chaganti R. S., Schonberg S., German J. 2022 Dec 9;13:983181. doi: 10.3389/fimmu.2022.983181. R01 CA162804/CA/NCI NIH HHS/United States, Abe T., Yoshimura A., Hosono Y., Tada S., Seki M., Enomoto T. (2011). The mutation spectrum in RECQL4 diseases. The https:// ensures that you are connecting to the Arguably, the most important DNA repair mechanisms are those that repair DNA double-strand breaks (DSBs) (Ciccia and Elledge, 2010; Ceccaldi et al., 2016; Scully et al., 2019). The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. WRN has also been found to interact with the following HR proteins: RAD51, RAD54, and RAD52 (Baynton et al., 2003; Otterlei et al., 2006; Lachapelle et al., 2011). Zhi L. Q., Ma W., Zhang H., Zeng S. X., Chen B. The HRDC domain of WRN plays a role in DNA binding (von Kobbe et al., 2003; Kitano et al., 2007) and is important for the recruitment of WRN protein to DSBs (Lan et al., 2005). (2020). RECQL5 has intrinsic ssDNA strand annealing activity, which is inhibited by ATP (Garcia et al., 2004; Ren et al., 2008). Front Cell Dev Biol. (2012b). In addition, WRN mutations are also associated with other tumors, such as breast cancer (Romanowicz et al., 2017), oral squamous cell carcinoma (Kuribayashi et al., 2019), and colorectal cancer (Lee et al., 2017; Zhunussova et al., 2019; Zimmer et al., 2020). Zhunussova G., Afonin G., Abdikerim S., Jumanov A., Perfilyeva A., Kaidarova D., et al. Epub 2023 Mar 21. This protein can also reverse damage from replication errors. DNA-PKcs promotes NHEJ and phosphorylates the histone H2AX and the chromatin remodeler KAP1 to promote chromatin relaxation proximal to the DSB to facilitate recruitment of the DNA damage response and repair machinery to the DNA damage site (Lu et al., 2019). Cheng W. H., Kusumoto R., Opresko P. L., Sui X., Huang S., Nicolette M. L., et al. van Brabant A. J., Ye T., Sanz M., German I. J., Ellis N. A., Holloman W. K. (2000). Multiple RPAs make WRN syndrome protein a superhelicase. Romanowicz H., Pyziak L., Jablonski F., Brys M., Forma E., Smolarz B. Kabotyanski E. B., Gomelsky L., Han J. O., Stamato T. D., Roth D. B. A., Savitsky P., Allerston C. K., Bizard A. H., Ozer O., Sarlos K., et al. sharing sensitive information, make sure youre on a federal The N-terminus of RECQL4 contains multiple functional domains, including both nuclear and mitochondrial targeting sequences (Burks et al., 2007; Croteau et al., 2012a). Human RecQ Helicases in DNA Repair, Recombination, (2019). Collaborating functions of BLM and DNA topoisomerase I in regulating human rDNA transcription. A., Miller S. P., Cheng W. H., et al. Interactions with shelterin proteins (TRF1, TRF2, and POT1) and resolution of secondary structures that are potential barriers to telomere replication are shown. Synthetic Lethal Interactions of RECQ Helicases. Bachrati C. Z., Borts R. H., Hickson I. D. (2006). Specifically, CDK1 and CDK2 phosphorylate RECQL4 on serines 89 and 251, and this facilitates the interaction between MRE11 and RECQL4 as well as RECQL4 recruitment to DSBs (Lu et al., 2017). Multiple genetically independent pathways have evolved that mediate the repair of DNA double-strand break (DSB), and RecQ helicases play pivotal roles in each of them. RECQ1 is required for cellular resistance to replication stress and catalyzes strand exchange on stalled replication fork structures. Patel D. S., Misenko S. M., Her J., Bunting S. F. (2017). 2022 Nov 26;23(23):14798. doi: 10.3390/ijms232314798. (2007). Sharma S., Phatak P., Stortchevoi A., Jasin M., Larocque J. R. (2012). Tervasmaki A., Mantere T., Hartikainen J. M., Kauppila S., Lee H. M., Koivuluoma S., et al. In addition, a small region between the RQC and HRDC domains promotes the ability of WRN to execute ssDNA annealing activity and oligomerization (Muftuoglu et al., 2008). This article focuses on the human RECQ helicases, five DNA-dependent helicases that play key roles in cellular physiology and WebRecent experiments have shown that the RecQ helicases function during distinct steps during DNA repair; DNA end resection, displacement-loop (D-loop) processing, branch These findings together demonstrate WRN as an important genome guardian to prevent diseases and as a potential drug target. Accessibility Sallmyr A., Tomkinson A. E., Rassool F. V. (2008). A role for BLM in double-strand break repair pathway choice: prevention of CtIP/Mre11-mediated alternative nonhomologous end-joining. In particular, Ku70/80 directly recruits DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to the DNA ends to form the DNA-PK complex, resulting in the activation of DNA-PKcs kinase activity (Davis et al., 2014). Popuri V, Tadokoro T, Croteau DL, Bohr VA. Crit Rev Biochem Mol Biol. Pannunzio N. R., Watanabe G., Lieber M. R. (2018). The accumulation of RECQL4 at DSBs is stimulated by both phosphorylation at Ser89 and Ser251 by CDK1 and CDK2 and ubiquitination by the DDB1-CUL4A E3 ubiquitin ligase (Lu et al., 2017). Jensen R. B., Carreira A., Kowalczykowski S. C. (2010). The human RecQ-like helicase BLM has a central role in DNA damage signaling, repair, replication, and telomere maintenance. (2017). Grabarz A., Guirouilh-Barbat J., Barascu A., Pennarun G., Genet D., Rass E., et al. Therefore, RECQL4 is crucial to maintain the integrity of the genome. SGS1, a homologue of the Blooms and Werners syndrome genes, is required for maintenance of genome stability in. Doherty K. M., Sommers J. Goto M., Imamura O., Kuromitsu J., Matsumoto T., Yamabe Y., Tokutake Y., et al. In support of this, an increased frequency of sister chromatid exchanges of >10-fold is used for the standard diagnosis of BS (Chaganti et al., 1974). RPA phosphorylation inhibits DNA resection. Werner syndrome protein and DNA replication. The factors and processes required for MMEJ and SSA are not well defined, but both initiate with the binding of PARP1 to the DSB ends and each requires DNA end resection (Bennardo et al., 2008; Xie et al., 2009; Lee-Theilen et al., 2011; Zhang and Jasin, 2011; Truong et al., 2013). Each of the five human RecQ helicases plays DEAD, DEAD/DEAH box helicase; Helicase C, helicase conserved C-terminal motif; RecQ-Zn-Bind, RecQ Zn2+-binding motif; RQC, RecQ-C-terminal domain; HRDC, helicase and RNase D-like C-terminal domain; CDT1, DNA replication factor CDT1 like; DUF1998, domain of unknown function (DUF1998); BLM_N, N-terminal region of Bloom syndrome protein; EXO, DNA_POLA_EXO1, 35 exonuclease domain; HTH_40, helix-turn-helix domain; SLD2, DNA replication and checkpoint protein; R4ZBD, RECQL4-Zn2+-binding motif; IRI, internal RNAPII-interacting domain; 51BD, RAD51-binding domain; SRI, SET2-RPB1 interaction motif. doi: 10.1371/journal.pone.0281524. Kikuchi K., Abdel-Aziz H. I., Taniguchi Y., Yamazoe M., Takeda S., Hirota K. (2009). Repair of DNA double-strand breaks by mammalian alternative end-joining pathways. official website and that any information you provide is encrypted (1997). (2000). Initiation of DNA replication requires the RECQL4 protein mutated in Rothmund-Thomson syndrome. Recent advances in understanding Werner syndrome. BLM and its budding yeast orthologue Sgs1 unwind double-stranded DNA intermediates. BLM helicase overexpressed in human gliomas contributes to diverse responses of human glioma cells to chemotherapy. These helicases play important roles in multiple cellular functions, including DNA replication, transcription, DNA repair, and telomere maintenance. Abbreviations: BER, base excision repair; DSBR, double-strand break repair; mRNA, messenger RNA; Topo, topoisomerase. (2020). Werner syndrome protein positively regulates XRCC4-like factor transcription. Abstract RecQ (2019). (2005). Polarity and bypass of DNA heterology during branch migration of Holliday junctions by human RAD54, BLM, and RECQ1 proteins. 8600 Rockville Pike Mutations in BLM lead to a rare autosomal-recessive genetic disorder, Bloom syndrome (BS; OMIM#210900). WebEach human RecQ helicase has a unique set of protein-interacting partners, and these interactions dictate its specialized functions in genome maintenance, including DNA repair, recombination, replication, and transcription. WRN efficiently unwinds duplex DNA with 3 or 5 ssDNA tails that are >10 nucleotides long, as well as unwinding duplex DNA duplex with shorter 3 ssDNA tails (BroshJr., Waheed and Sommers, 2002). Endogenous DNA double-strand breaks during DNA transactions: emerging insights and methods for genome-wide profiling. Direct and indirect roles of RECQL4 in modulating base excision repair capacity. (2002). Rossi M. L., Ghosh A. K., Kulikowicz T., Croteau D. L., Bohr V. A. Microhomology-mediated end joining and homologous recombination share the initial end resection step to repair DNA double-strand breaks in mammalian cells. Yang H., Li Q., Fan J., Holloman W. K., Pavletich N. P. (2005). RECQL4, located at chromosome 8q24.3, encodes a 1,208-amino acid protein, which possesses the highly conserved 3 to 5 helicase domain, but does not have the typical RQC and HRDC domains (Figure 3). Eukaryotic DNA ligases: structural and functional insights. Huang S., Lee L., Hanson N. B., Lenaerts C., Hoehn H., Poot M., et al. The https:// ensures that you are connecting to the Mutations in conserved functional domains of human RecQ Helicases are associated with diseases and cancer: a review. (2005). (2003). RECQL4C HCT116 cells (lacking the C-terminal domain) exhibit increased SSA activity and decreased MMEJ activity, and ectopic expression of RECQL4 increased HR and MMEJ but repressed SSA (Kohzaki et al., 2020).

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