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
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 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]
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]
↑ 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. PMID21265761.
This page is based on this Wikipedia article Text is available under the CC BY-SA 4.0 license; additional terms may apply. Images, videos and audio are available under their respective licenses.
