Biology:Helicase, POLQ-like

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


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.[1]

HelQ is a replication-linked repair helicase that preserves DNA integrity through helping in the repair of DNA that has become damaged.[2]

Gene

The gene encoding this enzyme, HELQ1, is located on chromosome 4q21.23 in humans.[3] It is associated with the polymerase pathway.[4]

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.[5][6][7]

Classification

Hel308 is part of DNA helicase Superfamily II.[1] Superfamily II helicases are the largest and most diverse group and comprise helicases that contribute to a vast selection of roles including transcription, DNA repair, chromatin rearrangement and RNA metabolism.[8][2] Human HelQ has been isolated and characterised as a ssDNA-dependent ATPase capable of translocating DNA with 3'-5' polarity.[3][9] The HelQ apoenzyme is activated through ATP hydrolysis and ssDNA and forms active dimers with translocase and helicase activity.[9][1][10]

Hel308 is found throughout archea and in some eukaryotes, including humans.[1][11] It contains twenty exons.[12]

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.[8] It is especially associated with DNA repair at locations where ssDNA has accumulated as a result of blocked replicative helicase or polymerase complexes.[9]

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.[2][13] 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.[8][14]

Hel308 is a large protein, 1101 amino acids in length,[3] 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.[15]

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.[9] N-HelQ lacks amino acid homology to other proteins and is thought to be intrinsically disordered.[6][9]

Expression

HelQ is found in many tissues, including the testes, ovaries, skeletal muscle, and heart, where its expression levels vary.[8][16] 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.[8] Overexpression of HelQ promotes resistance to treatments for ovarian cancers which are based on DNA crosslinking.[9][16]

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.[17] HelQ is also thought to have an additional role in germ line stability, as its deficiency affects fertility.[8]

Mutations in HEL308 are associated with cancer of the pharynx and mouth.[4]

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.[2] Number variations in helq are associated with ovarian cancers, with loss of HelQ in cells leading to a predisposition to cancer and infertility.[6][9][18]

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.[8]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 "Human HEL308 localizes to damaged replication forks and unwinds lagging strand structures". The Journal of Biological Chemistry 286 (18): 15832–15840. May 2011. doi:10.1074/jbc.M111.228189. PMID 21398521. 
  2. ↑ 2.0 2.1 2.2 2.3 Jenkins, Tabitha; Northall, Sarah; Bolt, Edward; Soultanas, Panos (2018-04-01). "It's good to unwind: how Hel308/HelQ helicases are good for health" (in en). The Biochemist 40 (2): 32–36. doi:10.1042/BIO04002032. ISSN 0954-982X. https://portlandpress.com/biochemist/article/40/2/32/449/It-s-good-to-unwind-how-Hel308-HelQ-helicases-are. 
  3. ↑ 3.0 3.1 3.2 "A human DNA helicase homologous to the DNA cross-link sensitivity protein Mus308". The Journal of Biological Chemistry 277 (10): 8716–8723. March 2002. doi:10.1074/jbc.M110271200. PMID 11751861. 
  4. ↑ 4.0 4.1 "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. July 2014. doi:10.1093/carcin/bgu075. PMID 24658182. 
  5. ↑ Marini, Federica; Wood, Richard D. (March 2002). "A Human DNA Helicase Homologous to the DNA Cross-link Sensitivity Protein Mus308" (in en). Journal of Biological Chemistry 277 (10): 8716–8723. doi:10.1074/jbc.M110271200. PMID 11751861. 
  6. ↑ 6.0 6.1 6.2 Northall, Sarah J.; Jenkins, Tabitha; Ptchelkine, Denis; Taresco, Vincenzo; Cooper, Christopher D. O.; Soultanas, Panos; Bolt, Edward L. (2019-01-04) (in en), Interaction of HelQ helicase with RPA modulates RPA-DNA binding and stimulates HelQ to unwind DNA through a protein roadblock, doi:10.1101/511758, http://biorxiv.org/lookup/doi/10.1101/511758, retrieved 2024-06-11 
  7. ↑ 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. http://www.elis.sk/index.php?page=shop.product_details&flypage=flypage.tpl&product_id=4890&category_id=128&option=com_virtuemart. 
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 8.6 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. PMID 37921071. 
  9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 9.6 Jenkins, Tabitha; Northall, Sarah J; Ptchelkine, Denis; Lever, Rebecca; Cubbon, Andrew; Betts, Hannah; Taresco, Vincenzo; Cooper, Christopher D O et al. (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" (in en). NAR Cancer 3 (1). doi:10.1093/narcan/zcaa043. ISSN 2632-8674. PMID 34316696. PMC 8210318. https://academic.oup.com/narcancer/article/doi/10.1093/narcan/zcaa043/6089195. 
  10. ↑ He, Liu; Lever, Rebecca; Cubbon, Andrew; Tehseen, Muhammad; Jenkins, Tabitha; Nottingham, Alice O; Horton, Anya; Betts, Hannah et al. (2023-02-28). "Interaction of human HelQ with DNA polymerase delta halts DNA synthesis and stimulates DNA single-strand annealing" (in en). Nucleic Acids Research 51 (4): 1740–1749. doi:10.1093/nar/gkad032. ISSN 0305-1048. PMID 36718939. PMC 9976902. https://academic.oup.com/nar/article/51/4/1740/7016441. 
  11. ↑ "Winged helix domains with unknown function in Hel308 and related helicases". Biochemical Society Transactions 39 (1): 140–144. January 2011. doi:10.1042/BST0390140. PMID 21265761. 
  12. ↑ "HELQ helicase, POLQ-like [ Homo sapiens (human) "]. National Institutes of Health. February 21, 2016. https://www.ncbi.nlm.nih.gov/gene/113510. 
  13. ↑ 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" (in en). DNA Repair 57: 125–132. doi:10.1016/j.dnarep.2017.07.005. PMID 28738244. https://linkinghub.elsevier.com/retrieve/pii/S1568786417301969. 
  14. ↑ 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" (in en). Nature Communications 12 (1): 7126. doi:10.1038/s41467-021-27408-z. ISSN 2041-1723. PMID 34880204. Bibcode: 2021NatCo..12.7126K. 
  15. ↑ "Structure of the DNA repair helicase hel308 reveals DNA binding and autoinhibitory domains". The Journal of Biological Chemistry 283 (8): 5118–5126. February 2008. doi:10.1074/jbc.M707548200. PMID 18056710. 
  16. ↑ 16.0 16.1 Long, Jing; Zhu, Jun-You; Liu, Yong-Bin; Fu, Kun; Tian, Yan; Li, Pei-Yao; Yang, Wen-Qing; Yang, Si-Yu et al. (May 2018). "Helicase POLQ-like (HELQ) as a novel indicator of platinum-based chemoresistance for epithelial ovarian cancer" (in en). Gynecologic Oncology 149 (2): 341–349. doi:10.1016/j.ygyno.2018.03.006. PMID 29572031. 
  17. ↑ 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" (in en). Nature Communications 4 (1): 2338. doi:10.1038/ncomms3338. ISSN 2041-1723. PMID 24005565. Bibcode: 2013NatCo...4.2338T. 
  18. ↑ 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" (in en). Oncology Letters 12 (6): 4439–4444. doi:10.3892/ol.2016.5224. ISSN 1792-1074. PMID 28101207. 



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