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Helicase, POLQ-like

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HELQ
Identifiers
AliasesHELQ, HEL308, helicase, POLQ-like, helicase, POLQ like
External IDsOMIM: 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 MbChr 5: 100.91 – 100.95 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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]

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

Gene[edit]

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

Nomenclature[edit]

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[edit]

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[edit]

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[edit]

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[edit]

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[edit]

References[edit]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000163312 – Ensembl, May 2017
  2. ^ a b c 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. ^ a b c d 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. ^ a b c d 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. ^ a b c 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. ^ a b 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. ^ a b c 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. ^ a b c d e f g 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. ^ a b c d e f g 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. ^ a b 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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