Helicase, POLQ-like

Last updated
HELQ
Identifiers
Aliases HELQ , HEL308, helicase, POLQ-like, helicase, POLQ like
External IDs OMIM: 606769; MGI: 2176740; HomoloGene: 14667; GeneCards: HELQ; OMA:HELQ - orthologs
Orthologs
SpeciesHumanMouse
Entrez

113510

191578

Ensembl

ENSG00000163312

ENSMUSG00000035266

UniProt

Q8TDG4

Q2VPA6

RefSeq (mRNA)

NM_001081107
NM_180984

RefSeq (protein)

NP_001074576

Location (UCSC) Chr 4: 83.41 – 83.46 Mb Chr 5: 100.91 – 100.95 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Helicase, POLQ-like, also known as Helicase Q (HELQ), HEL308 and Holliday junction migration protein, encoded by the gene HELQ1, is a DNA helicase found in humans, archea and many other organisms. [5]

Contents

HelQ is a replication-linked repair helicase that preserves DNA integrity through helping in the repair of DNA that has become damaged. [6]

Gene

The gene encoding this enzyme, HELQ1, is located on chromosome 4q21.23 in humans. [7] It is associated with the polymerase pathway. [8]

Nomenclature

When first reported, Helicase Q was called "Holliday junction migration protein."

HelQ was originally identified and purified by Marini and Wood when they were looking for human homologues of Mus308, a protein involved in inter-strand crosslink repair. PolQ, also known as Polymerase θ, encodes a polymerase domain homologous to Mus308. HelQ contains the homologous helicase domain. [9] [10] [11]

Classification

Hel308 is part of DNA helicase Superfamily II. [5] Superfamily II helicases are the largest and most diverse group and comprise of helicases that contribute to a vast selection of roles including transcription, DNA repair, chromatin rearrangement and RNA metabolism. [12] [6] Human HelQ has been isolated and characterised as a ssDNA-dependent ATPase capable of translocating DNA with 3’-5’ polarity. [7] [13] The HelQ apoenzyme is activated through ATP hydrolysis and ssDNA and forms active dimers with translocase and helicase activity. [13] [5] [14]

Hel308 is found throughout archea and in some eukaryotes, including humans. [5] [15] It contains twenty exons. [16]

Structure and function

Helicase Q's principal role is in the DNA repair. HelQ is very highly conserved and is thought to contribute to a variety of DNA processes, such as DNA repair, unwinding and strand annealing. [12] It is especially associated with DNA repair at locations where ssDNA has accumulated as a result of blocked replicative helicase or polymerase complexes. [13]

A known function of HelQ is its participation in DNA repair at replication forks via interactions with homologous recombination proteins, such as replication protein A and Rad51 and Rad51 paralogues BCDX2. [6] [17] There are many pathways which both recognise and repair DNA damage and/or lesions, and HelQ is implicated in nucleotide excision repair, interstrand cross-links and double-strand break repair to carry out its role. HelQ is thought to be essential for the function of synthesis-dependent strand annealing (a type of homologous recombination), micro-homology mediated end joining of G4-induced double-strand breaks and single-strand annealing in genome stability and tumour avoidance. [12] [18]

Hel308 is a large protein, 1101 amino acids in length, [7] with five separate domains. The third and fourth domains form a large central pore that holds single-stranded DNA. Its fifth domain acts as a brake by securing the single-strand DNA protruding through this pore. [19]

Residues 1-241 of the N-terminal end of the protein, termed N-HelQ, is only present in mammalian HelQ, but is not found in archaea and prokaryotes. A PWI-like fold is present in N-HelQ and shares homology with the PWI-fold in yeast Ski2 like helicase Brr2. [13] N-HelQ lacks amino acid homology to other proteins and is thought to be intrinsically disordered. [10] [13]

Expression

HelQ is found in many tissues, including the testes, ovaries, skeletal muscle, and heart, where its expression levels vary. [12] [20] How HelQ acts is reliant on the tissue it is located in. High levels of HelQ are tumour suppressing and correspond to a better patient prognosis in osteosarcoma and non-small cell lung cancer, but high levels of HelQ in ovarian cancer is associated with poor patient prognosis. [12] Overexpression of HelQ promotes resistance to treatments for ovarian cancers which are based on DNA crosslinking. [13] [20]

Clinical significance

HelQ's mutations and gene deletions cause a change in the efficacy of DNA replication, as well as causing hypersensitivity of cells to DNA cross-linking agents, which result in blockage of DNA replication. [21] HelQ is also thought to have an additional role in germ line stability, as its deficiency affects fertility. [12]

Mutations in HEL308 are associated with cancer of the pharynx and mouth. [8]

In the clinic, HelQ defects have been associated with breast and ovarian cancers, oesophageal squamous carcinoma and reproductive issues, although the precise, mechanistic links are currently unknown. [6] Number variations in helq are associated with ovarian cancers, with loss of HelQ in cells leading to a predisposition to cancer and infertility. [10] [13] [22]

The wide range of roles HelQ plays in tumourigenesis, resulting from its involvement in tumour proliferation, metastasis, platinum resistance, cell-cycle regulation and DNA damage response, emphasise its potential as a drug target for novel cancer treatments. [12]

See also

Related Research Articles

DNA primase is an enzyme involved in the replication of DNA and is a type of RNA polymerase. Primase catalyzes the synthesis of a short RNA segment called a primer complementary to a ssDNA template. After this elongation, the RNA piece is removed by a 5' to 3' exonuclease and refilled with DNA.

<span class="mw-page-title-main">Helicase</span> Class of enzymes to unpack an organisms genes

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, separating two hybridized nucleic acid strands, using energy from ATP hydrolysis. There are many helicases, representing the great variety of processes in which strand separation must be catalyzed. Approximately 1% of eukaryotic genes code for helicases.

<span class="mw-page-title-main">DNA repair</span> Cellular mechanism

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 damage, resulting in tens of thousands of individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur. This can eventually lead to malignant tumors, or cancer as per the two-hit hypothesis.

RecQ helicase is a family of helicase enzymes initially found in Escherichia coli 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.

<span class="mw-page-title-main">Homologous recombination</span> Genetic recombination between identical or highly similar strands of genetic material

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.

<span class="mw-page-title-main">Werner syndrome helicase</span> Enzyme found in humans

Werner syndrome ATP-dependent helicase, also known as DNA helicase, RecQ-like type 3, is an enzyme that in humans is encoded by the WRN gene. WRN is a member of the RecQ Helicase family. Helicase enzymes generally unwind and separate double-stranded DNA. These activities are necessary before DNA can be copied in preparation for cell division. Helicase enzymes are also critical for making a blueprint of a gene for protein production, a process called transcription. Further evidence suggests that Werner protein plays a critical role in repairing DNA. Overall, this protein helps maintain the structure and integrity of a person's DNA.

<span class="mw-page-title-main">Replisome</span> Molecular complex

The replisome is a complex molecular machine that carries out replication of DNA. The replisome first unwinds double stranded DNA into two single strands. For each of the resulting single strands, a new complementary sequence of DNA is synthesized. The total result is formation of two new double stranded DNA sequences that are exact copies of the original double stranded DNA sequence.

Recombinases are genetic recombination enzymes.

<span class="mw-page-title-main">Eukaryotic DNA replication</span> DNA replication in eukaryotic organisms

Eukaryotic DNA replication is a conserved mechanism that restricts DNA replication to once per cell cycle. Eukaryotic DNA replication of chromosomal DNA is central for the duplication of a cell and is necessary for the maintenance of the eukaryotic genome.

<span class="mw-page-title-main">Minichromosome maintenance</span>

The minichromosome maintenance protein complex (MCM) is a DNA helicase essential for genomic DNA replication. Eukaryotic MCM consists of six gene products, Mcm2–7, which form a heterohexamer. As a critical protein for cell division, MCM is also the target of various checkpoint pathways, such as the S-phase entry and S-phase arrest checkpoints. Both the loading and activation of MCM helicase are strictly regulated and are coupled to cell growth cycles. Deregulation of MCM function has been linked to genomic instability and a variety of carcinomas.

<span class="mw-page-title-main">ERCC6</span> Gene of the species Homo sapiens

DNA excision repair protein ERCC-6 is a protein that in humans is encoded by the ERCC6 gene. The ERCC6 gene is located on the long arm of chromosome 10 at position 11.23.

<span class="mw-page-title-main">BRIP1</span> Mammalian protein found in Homo sapiens

Fanconi anemia group J protein is a protein that in humans is encoded by the BRCA1-interacting protein 1 (BRIP1) gene.

<span class="mw-page-title-main">POLQ</span> Protein-coding gene in the species Homo sapiens

DNA polymerase theta is an enzyme that in humans is encoded by the POLQ gene. This polymerase plays a key role in one of the three major double strand break repair pathways: theta-mediated end joining (TMEJ). Most double-strand breaks are repaired by non-homologous end joining (NHEJ) or homology directed repair (HDR). However, in some contexts, NHEJ and HR are insufficient and TMEJ is the only solution to repair the break. TMEJ is often described as alternative NHEJ, but differs in that it lacks a requirement for the Ku heterodimer, and it can only act on resected DNA ends. Following annealing of short regions on the DNA overhangs, DNA polymerase theta catalyzes template-dependent DNA synthesis across the broken ends, stabilizing the paired structure.

PcrA, standing for plasmid copy reduced is a helicase that was originally discovered in a screen for chromosomally encoded genes that are affected in plasmid rolling circle replication in the Gram-positive pathogen Staphylococcus aureus.

<span class="mw-page-title-main">FANCM</span> Mammalian protein found in Homo sapiens

Fanconi anemia, complementation group M, also known as FANCM is a human gene. It is an emerging target in cancer therapy, in particular cancers with specific genetic deficiencies.

Microhomology-mediated end joining (MMEJ), also known as alternative nonhomologous end-joining (Alt-NHEJ) is one of the pathways for repairing double-strand breaks in DNA. As reviewed by McVey and Lee, the foremost distinguishing property of MMEJ is the use of microhomologous sequences during the alignment of broken ends before joining, thereby resulting in deletions flanking the original break. MMEJ is frequently associated with chromosome abnormalities such as deletions, translocations, inversions and other complex rearrangements.

<span class="mw-page-title-main">PARP inhibitor</span> Pharmacological enzyme inhibitors of poly (ADP-ribose) polymerases

PARP inhibitors are a group of pharmacological inhibitors of the enzyme poly ADP ribose polymerase (PARP).

<span class="mw-page-title-main">Synthesis-dependent strand annealing</span>

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 1983 was favored by many researchers. In 1994, studies of double-strand gap repair in Drosophila were found to be incompatible with the double-Holliday junction model, leading researchers to propose a model they called synthesis-dependent strand annealing. Subsequent studies of meiotic recombination in S. cerevisiae found that non-crossover products appear earlier than double-Holliday junctions or crossover products, challenging the previous notion that both crossover and non-crossover products are produced by double-Holliday junctions and leading the authors to propose that non-crossover products are generated through SDSA.

<span class="mw-page-title-main">Single-stranded binding protein</span>

Single-stranded binding proteins (SSBs) are a class of proteins that have been identified in both viruses and organisms from bacteria to humans.

<span class="mw-page-title-main">Double-strand break repair model</span>

A double-strand break repair model refers to the various models of pathways that cells undertake to repair double strand-breaks (DSB). DSB repair is an important cellular process, as the accumulation of unrepaired DSB could lead to chromosomal rearrangements, tumorigenesis or even cell death. In human cells, there are two main DSB repair mechanisms: Homologous recombination (HR) and non-homologous end joining (NHEJ). HR relies on undamaged template DNA as reference to repair the DSB, resulting in the restoration of the original sequence. NHEJ modifies and ligates the damaged ends regardless of homology. In terms of DSB repair pathway choice, most mammalian cells appear to favor NHEJ rather than HR. This is because the employment of HR may lead to gene deletion or amplification in cells which contains repetitive sequences. In terms of repair models in the cell cycle, HR is only possible during the S and G2 phases, while NHEJ can occur throughout whole process. These repair pathways are all regulated by the overarching DNA damage response mechanism. Besides HR and NHEJ, there are also other repair models which exists in cells. Some are categorized under HR, such as synthesis-dependent strain annealing, break-induced replication, and single-strand annealing; while others are an entirely alternate repair model, namely, the pathway microhomology-mediated end joining (MMEJ).

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000163312 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000035266 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 3 4 Tafel AA, Wu L, McHugh PJ (May 2011). "Human HEL308 localizes to damaged replication forks and unwinds lagging strand structures". The Journal of Biological Chemistry. 286 (18): 15832–15840. doi: 10.1074/jbc.M111.228189 . PMC   3091193 . PMID   21398521.
  6. 1 2 3 4 Jenkins, Tabitha; Northall, Sarah; Bolt, Edward; Soultanas, Panos (2018-04-01). "It's good to unwind: how Hel308/HelQ helicases are good for health". The Biochemist. 40 (2): 32–36. doi:10.1042/BIO04002032. ISSN   0954-982X.
  7. 1 2 3 Marini F, Wood RD (March 2002). "A human DNA helicase homologous to the DNA cross-link sensitivity protein Mus308". The Journal of Biological Chemistry. 277 (10): 8716–8723. doi: 10.1074/jbc.M110271200 . PMID   11751861.
  8. 1 2 Babron MC, Kazma R, Gaborieau V, McKay J, Brennan P, Sarasin A, Benhamou S (July 2014). "Genetic variants in DNA repair pathways and risk of upper aerodigestive tract cancers: combined analysis of data from two genome-wide association studies in European populations". Carcinogenesis. 35 (7): 1523–1527. doi: 10.1093/carcin/bgu075 . PMID   24658182.
  9. ↑ Marini, Federica; Wood, Richard D. (March 2002). "A Human DNA Helicase Homologous to the DNA Cross-link Sensitivity Protein Mus308". Journal of Biological Chemistry. 277 (10): 8716–8723. doi: 10.1074/jbc.M110271200 . PMID   11751861.
  10. 1 2 3 Northall, Sarah J.; Jenkins, Tabitha; Ptchelkine, Denis; Taresco, Vincenzo; Cooper, Christopher D. O.; Soultanas, Panos; Bolt, Edward L. (2019-01-04), Interaction of HelQ helicase with RPA modulates RPA-DNA binding and stimulates HelQ to unwind DNA through a protein roadblock, doi:10.1101/511758 , retrieved 2024-06-11
  11. ↑ Han, X.; Zhao, L.; Li, X. (2016). "HELQ in cancer and reproduction". Neoplasma. 63 (6): 825–835. doi:10.4149/neo_2016_601. PMID   27565320.
  12. 1 2 3 4 5 6 7 Tang, Nan; Wen, Weilun; Liu, Zhihe; Xiong, Xifeng; Wu, Yanhua (2023-11-02). "HELQ as a DNA helicase: Its novel role in normal cell function and tumorigenesis (Review)". Oncology Reports. 50 (6). doi:10.3892/or.2023.8657. ISSN   1021-335X. PMC   10652244 . PMID   37921071.
  13. 1 2 3 4 5 6 7 Jenkins, Tabitha; Northall, Sarah J; Ptchelkine, Denis; Lever, Rebecca; Cubbon, Andrew; Betts, Hannah; Taresco, Vincenzo; Cooper, Christopher D O; McHugh, Peter J; Soultanas, Panos; Bolt, Edward L (2021-01-12). "The HelQ human DNA repair helicase utilizes a PWI-like domain for DNA loading through interaction with RPA, triggering DNA unwinding by the HelQ helicase core". NAR Cancer. 3 (1): zcaa043. doi:10.1093/narcan/zcaa043. ISSN   2632-8674. PMC   8210318 . PMID   34316696.
  14. ↑ He, Liu; Lever, Rebecca; Cubbon, Andrew; Tehseen, Muhammad; Jenkins, Tabitha; Nottingham, Alice O; Horton, Anya; Betts, Hannah; Fisher, Martin; Hamdan, Samir M; Soultanas, Panos; Bolt, Edward L (2023-02-28). "Interaction of human HelQ with DNA polymerase delta halts DNA synthesis and stimulates DNA single-strand annealing". Nucleic Acids Research. 51 (4): 1740–1749. doi:10.1093/nar/gkad032. ISSN   0305-1048. PMC   9976902 . PMID   36718939.
  15. ↑ Woodman IL, Bolt EL (January 2011). "Winged helix domains with unknown function in Hel308 and related helicases". Biochemical Society Transactions. 39 (1): 140–144. doi:10.1042/BST0390140. PMID   21265761.
  16. ↑ "HELQ helicase, POLQ-like [ Homo sapiens (human) ]". NCBI. National Institutes of Health. February 21, 2016.
  17. ↑ Northall, Sarah J.; Buckley, Ryan; Jones, Nathan; Penedo, J. Carlos; Soultanas, Panos; Bolt, Edward L. (September 2017). "DNA binding and unwinding by Hel308 helicase requires dual functions of a winged helix domain". DNA Repair. 57: 125–132. doi:10.1016/j.dnarep.2017.07.005. PMID   28738244.
  18. ↑ Kamp, J. A.; Lemmens, B. B. L. G.; Romeijn, R. J.; Changoer, S. C.; van Schendel, R.; Tijsterman, M. (2021-12-08). "Helicase Q promotes homology-driven DNA double-strand break repair and prevents tandem duplications". Nature Communications. 12 (1): 7126. Bibcode:2021NatCo..12.7126K. doi:10.1038/s41467-021-27408-z. ISSN   2041-1723. PMC   8654963 . PMID   34880204.
  19. ↑ Richards JD, Johnson KA, Liu H, McRobbie AM, McMahon S, Oke M, et al. (February 2008). "Structure of the DNA repair helicase hel308 reveals DNA binding and autoinhibitory domains". The Journal of Biological Chemistry. 283 (8): 5118–5126. doi: 10.1074/jbc.M707548200 . PMC   3434800 . PMID   18056710.
  20. 1 2 Long, Jing; Zhu, Jun-You; Liu, Yong-Bin; Fu, Kun; Tian, Yan; Li, Pei-Yao; Yang, Wen-Qing; Yang, Si-Yu; Yin, Ji-Ye; Yin, Gang; Zhang, Yu (May 2018). "Helicase POLQ-like (HELQ) as a novel indicator of platinum-based chemoresistance for epithelial ovarian cancer". Gynecologic Oncology. 149 (2): 341–349. doi:10.1016/j.ygyno.2018.03.006. PMID   29572031.
  21. ↑ Takata, Kei-ichi; Reh, Shelley; Tomida, Junya; Person, Maria D.; Wood, Richard D. (2013-09-04). "Human DNA helicase HELQ participates in DNA interstrand crosslink tolerance with ATR and RAD51 paralogs". Nature Communications. 4 (1): 2338. Bibcode:2013NatCo...4.2338T. doi:10.1038/ncomms3338. ISSN   2041-1723. PMC   3778836 . PMID   24005565.
  22. ↑ Li, Ya-Ping; Yang, Jun-Juan; Xu, Hui; Guo, En-Yu; Yu, Yan (December 2016). "Structure-function analysis of DNA helicase HELQ: A new diagnostic marker in ovarian cancer". Oncology Letters. 12 (6): 4439–4444. doi:10.3892/ol.2016.5224. ISSN   1792-1074. PMC   5228290 . PMID   28101207.
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