{{Short description|Protein-coding gene in the species Homo sapiens}} {{Infobox gene}}
'''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.<ref name="Tafel_2011">{{cite journal |vauthors=Tafel AA, Wu L, McHugh PJ |date=May 2011 |title=Human HEL308 localizes to damaged replication forks and unwinds lagging strand structures |journal=The Journal of Biological Chemistry |volume=286 |issue=18 |pages=15832–15840 |doi=10.1074/jbc.M111.228189 |pmc=3091193 |pmid=21398521 |doi-access=free}}</ref>
HelQ is a replication-linked repair helicase that preserves DNA integrity through helping in the repair of DNA that has become damaged.<ref name=":0">{{Cite journal |last1=Jenkins |first1=Tabitha |last2=Northall |first2=Sarah |last3=Bolt |first3=Edward |last4=Soultanas |first4=Panos |date=2018-04-01 |title=It's good to unwind: how Hel308/HelQ helicases are good for health |url=https://portlandpress.com/biochemist/article/40/2/32/449/It-s-good-to-unwind-how-Hel308-HelQ-helicases-are |journal=The Biochemist |language=en |volume=40 |issue=2 |pages=32–36 |doi=10.1042/BIO04002032 |issn=0954-982X|doi-access=free }}</ref>
== Gene ==
The gene encoding this enzyme, ''HELQ1'', is located on chromosome 4q21.23 in humans.<ref name="Marini_2001">{{cite journal | vauthors = Marini F, Wood RD | title = A human DNA helicase homologous to the DNA cross-link sensitivity protein Mus308 | journal = The Journal of Biological Chemistry | volume = 277 | issue = 10 | pages = 8716–8723 | date = March 2002 | pmid = 11751861 | doi = 10.1074/jbc.M110271200 | doi-access = free }}</ref> It is associated with the polymerase pathway.<ref name="Babron_2014"/>
== 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.<ref>{{Cite journal |last1=Marini |first1=Federica |last2=Wood |first2=Richard D. |date=March 2002 |title=A Human DNA Helicase Homologous to the DNA Cross-link Sensitivity Protein Mus308 |journal=Journal of Biological Chemistry |language=en |volume=277 |issue=10 |pages=8716–8723 |doi=10.1074/jbc.M110271200|doi-access=free |pmid=11751861 }}</ref><ref name=":1">{{cite bioRxiv |last1=Northall |first1=Sarah J. |title=Interaction of HelQ helicase with RPA modulates RPA-DNA binding and stimulates HelQ to unwind DNA through a protein roadblock |date=2019-01-04 |language=en |biorxiv=10.1101/511758 |last2=Jenkins |first2=Tabitha |last3=Ptchelkine |first3=Denis |last4=Taresco |first4=Vincenzo |last5=Cooper |first5=Christopher D. O. |last6=Soultanas |first6=Panos |last7=Bolt |first7=Edward L.}}</ref><ref>{{Cite journal |last1=Han |first1=X. |last2=Zhao |first2=L. |last3=Li |first3=X. |date=2016 |title=HELQ in cancer and reproduction |url=http://www.elis.sk/index.php?page=shop.product_details&flypage=flypage.tpl&product_id=4890&category_id=128&option=com_virtuemart |journal=Neoplasma |volume=63 |issue=6 |pages=825–835 |doi=10.4149/neo_2016_601|pmid=27565320 }}</ref>
== Classification ==
Hel308 is part of DNA helicase Superfamily II.<ref name="Tafel_2011"/> 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.<ref name=":2">{{Cite journal |last1=Tang |first1=Nan |last2=Wen |first2=Weilun |last3=Liu |first3=Zhihe |last4=Xiong |first4=Xifeng |last5=Wu |first5=Yanhua |date=2023-11-02 |title=HELQ as a DNA helicase: Its novel role in normal cell function and tumorigenesis (Review) |journal=Oncology Reports |volume=50 |issue=6 |article-number=220 |doi=10.3892/or.2023.8657 |issn=1021-335X |pmc=10652244 |pmid=37921071}}</ref><ref name=":0" /> Human HelQ has been isolated and characterised as a ssDNA-dependent ATPase capable of translocating DNA with 3'-5' polarity.<ref name="Marini_2001" /><ref name=":3">{{Cite journal |last1=Jenkins |first1=Tabitha |last2=Northall |first2=Sarah J |last3=Ptchelkine |first3=Denis |last4=Lever |first4=Rebecca |last5=Cubbon |first5=Andrew |last6=Betts |first6=Hannah |last7=Taresco |first7=Vincenzo |last8=Cooper |first8=Christopher D O |last9=McHugh |first9=Peter J |last10=Soultanas |first10=Panos |last11=Bolt |first11=Edward L |date=2021-01-12 |title=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 |url=https://academic.oup.com/narcancer/article/doi/10.1093/narcan/zcaa043/6089195 |journal=NAR Cancer |language=en |volume=3 |issue=1 |article-number=zcaa043 |doi=10.1093/narcan/zcaa043 |issn=2632-8674 |pmc=8210318 |pmid=34316696}}</ref> The HelQ apoenzyme is activated through ATP hydrolysis and ssDNA and forms active dimers with translocase and helicase activity.<ref name=":3" /><ref name="Tafel_2011" /><ref>{{Cite journal |last1=He |first1=Liu |last2=Lever |first2=Rebecca |last3=Cubbon |first3=Andrew |last4=Tehseen |first4=Muhammad |last5=Jenkins |first5=Tabitha |last6=Nottingham |first6=Alice O |last7=Horton |first7=Anya |last8=Betts |first8=Hannah |last9=Fisher |first9=Martin |last10=Hamdan |first10=Samir M |last11=Soultanas |first11=Panos |last12=Bolt |first12=Edward L |date=2023-02-28 |title=Interaction of human HelQ with DNA polymerase delta halts DNA synthesis and stimulates DNA single-strand annealing |url=https://academic.oup.com/nar/article/51/4/1740/7016441 |journal=Nucleic Acids Research |language=en |volume=51 |issue=4 |pages=1740–1749 |doi=10.1093/nar/gkad032 |issn=0305-1048 |pmc=9976902 |pmid=36718939}}</ref>
Hel308 is found throughout archea and in some eukaryotes, including humans.<ref name="Tafel_2011" /><ref name="Woodman_2011">{{cite journal |vauthors=Woodman IL, Bolt EL |date=January 2011 |title=Winged helix domains with unknown function in Hel308 and related helicases |journal=Biochemical Society Transactions |volume=39 |issue=1 |pages=140–144 |doi=10.1042/BST0390140 |pmid=21265761}}</ref> It contains twenty exons.<ref name="NCBI">{{cite web|date=February 21, 2016|title=HELQ helicase, POLQ-like [ Homo sapiens (human) ]|url=https://www.ncbi.nlm.nih.gov/gene/113510|website=NCBI|publisher=National Institutes of Health}}</ref>
== 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.<ref name=":2" /> It is especially associated with DNA repair at locations where ssDNA has accumulated as a result of blocked replicative helicase or polymerase complexes.<ref name=":3" />
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.<ref name=":0" /><ref>{{Cite journal |last1=Northall |first1=Sarah J. |last2=Buckley |first2=Ryan |last3=Jones |first3=Nathan |last4=Penedo |first4=J. Carlos |last5=Soultanas |first5=Panos |last6=Bolt |first6=Edward L. |date=September 2017 |title=DNA binding and unwinding by Hel308 helicase requires dual functions of a winged helix domain |url=https://linkinghub.elsevier.com/retrieve/pii/S1568786417301969 |journal=DNA Repair |language=en |volume=57 |pages=125–132 |doi=10.1016/j.dnarep.2017.07.005|pmid=28738244 |hdl=10023/15453 |hdl-access=free }}</ref> 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.<ref name=":2" /><ref>{{Cite journal |last1=Kamp |first1=J. A. |last2=Lemmens |first2=B. B. L. G. |last3=Romeijn |first3=R. J. |last4=Changoer |first4=S. C. |last5=van Schendel |first5=R. |last6=Tijsterman |first6=M. |date=2021-12-08 |title=Helicase Q promotes homology-driven DNA double-strand break repair and prevents tandem duplications |journal=Nature Communications |language=en |volume=12 |issue=1 |page=7126 |doi=10.1038/s41467-021-27408-z |issn=2041-1723 |pmc=8654963 |pmid=34880204|bibcode=2021NatCo..12.7126K }}</ref>
Hel308 is a large protein, 1101 amino acids in length,<ref name="Marini_2001" /> 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.<ref name="Richards_2007">{{cite journal | vauthors = Richards JD, Johnson KA, Liu H, McRobbie AM, McMahon S, Oke M, Carter L, Naismith JH, White MF | display-authors = 6 | title = Structure of the DNA repair helicase hel308 reveals DNA binding and autoinhibitory domains | journal = The Journal of Biological Chemistry | volume = 283 | issue = 8 | pages = 5118–5126 | date = February 2008 | pmid = 18056710 | pmc = 3434800 | doi = 10.1074/jbc.M707548200 | doi-access = free }}</ref>
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.<ref name=":3" /> N-HelQ lacks amino acid homology to other proteins and is thought to be intrinsically disordered.<ref name=":1" /><ref name=":3" />
== Expression == HelQ is found in many tissues, including the testes, ovaries, skeletal muscle, and heart, where its expression levels vary.<ref name=":2" /><ref name=":4">{{Cite journal |last1=Long |first1=Jing |last2=Zhu |first2=Jun-You |last3=Liu |first3=Yong-Bin |last4=Fu |first4=Kun |last5=Tian |first5=Yan |last6=Li |first6=Pei-Yao |last7=Yang |first7=Wen-Qing |last8=Yang |first8=Si-Yu |last9=Yin |first9=Ji-Ye |last10=Yin |first10=Gang |last11=Zhang |first11=Yu |date=May 2018 |title=Helicase POLQ-like (HELQ) as a novel indicator of platinum-based chemoresistance for epithelial ovarian cancer |journal=Gynecologic Oncology |language=en |volume=149 |issue=2 |pages=341–349 |doi=10.1016/j.ygyno.2018.03.006|pmid=29572031 |doi-access=free }}</ref> 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.<ref name=":2" /> Overexpression of HelQ promotes resistance to treatments for ovarian cancers which are based on DNA crosslinking.<ref name=":3" /><ref name=":4" />
== 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.<ref>{{Cite journal |last1=Takata |first1=Kei-ichi |last2=Reh |first2=Shelley |last3=Tomida |first3=Junya |last4=Person |first4=Maria D. |last5=Wood |first5=Richard D. |date=2013-09-04 |title=Human DNA helicase HELQ participates in DNA interstrand crosslink tolerance with ATR and RAD51 paralogs |journal=Nature Communications |language=en |volume=4 |issue=1 |page=2338 |doi=10.1038/ncomms3338 |issn=2041-1723 |pmc=3778836 |pmid=24005565|bibcode=2013NatCo...4.2338T }}</ref> HelQ is also thought to have an additional role in germ line stability, as its deficiency affects fertility.<ref name=":2" />
Mutations in ''HEL308'' are associated with cancer of the pharynx and mouth.<ref name="Babron_2014">{{cite journal | vauthors = Babron MC, Kazma R, Gaborieau V, McKay J, Brennan P, Sarasin A, Benhamou S | title = 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 | journal = Carcinogenesis | volume = 35 | issue = 7 | pages = 1523–1527 | date = July 2014 | pmid = 24658182 | doi = 10.1093/carcin/bgu075 | doi-access = free }}</ref>
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.<ref name=":0" /> Number variations in ''helq'' are associated with ovarian cancers, with loss of HelQ in cells leading to a predisposition to cancer and infertility.<ref name=":1" /><ref name=":3" /><ref>{{Cite journal |last1=Li |first1=Ya-Ping |last2=Yang |first2=Jun-Juan |last3=Xu |first3=Hui |last4=Guo |first4=En-Yu |last5=Yu |first5=Yan |date=December 2016 |title=Structure-function analysis of DNA helicase HELQ: A new diagnostic marker in ovarian cancer |journal=Oncology Letters |language=en |volume=12 |issue=6 |pages=4439–4444 |doi=10.3892/ol.2016.5224 |issn=1792-1074 |pmc=5228290 |pmid=28101207}}</ref>
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.<ref name=":2" />
== See also == * Helicase * DNA repair * DNA replication
== References == {{Reflist|33em}}
Category:Human proteins Category:DNA Category:DNA repair Category:Helicases