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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.

ABSTRACT: Genome instability is a characteristic enabling factor for carcinogenesis. HelQ helicase is a component of human DNA maintenance systems that prevent or reverse genome instability arising during DNA replication. Here, we provide details of the molecular mechanisms that underpin HelQ function-its recruitment onto ssDNA through interaction with replication protein A (RPA), and subsequent translocation of HelQ along ssDNA. We describe for the first time a functional role for the non-catalytic N-terminal region of HelQ, by identifying and characterizing its PWI-like domain. We present evidence that this domain of HelQ mediates interaction with RPA that orchestrates loading of the helicase domains onto ssDNA. Once HelQ is loaded onto the ssDNA, ATP-Mg²⁺ binding in the catalytic site activates the helicase core and triggers translocation along ssDNA as a dimer. Furthermore, we identify HelQ-ssDNA interactions that are critical for the translocation mechanism. Our data are novel and detailed insights into the mechanisms of HelQ function relevant for understanding how human cells avoid genome instability provoking cancers, and also how cells can gain resistance to treatments that rely on DNA crosslinking agents.

SUBMITTER: Jenkins T

PROVIDER: S-EPMC8210318 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:It has been previously reported that a deficiency of the helicase, POLQ-like (HELQ) gene increases the risk of ovarian cancer. The present study aimed to explore the structure-function association of HELQ and discuss the effect of molecular structure on the occurrence of tumors. ExPASy tools were employed to analyze the physicochemical properties and secondary structure of the genes. PHYRE2 Protein Fold Recognition Server was used to construct the three-dimensional model and find the ligand-binding sites of HELQ. In addition, the potential functions corresponding to these structures were excavated by comparing and analyzing protein domains. The HELQ protein is located in the cytoplasm (56.5%) and nucleus (21.7%). HELQ has 4 conserved domains, consisting of DEXDc, HELICc, HHH_5 and PRK02362, which contain the adenosine triphosphate (ATP) binding site, nucleotide binding region and putative Mg2+ binding site. In the secondary structure, it was found that HELQ was mainly composed of ? helix (46.68%) and random coils (43.05%), with only 10.26% extended strand. According to 3DLigandSite Server, the ligand binding sites appeared in ILE333, LYS335, TYR337, SER362, LEU367, LYS397, GLN340, GLY363, GLY364 and ASN678 of the amino acid sequence. Among the functional protein association networks, regulator of telomere elongation helicase 1, family with sequence similarity 175 member A, small ubiquitin-like modifier 1, DNA polymerase ? and coiled-coil domain containing 158 were involved and co-expressed with HELQ. PredictProtein analysis indicated that the dominant functions of HELQ were ATP-dependent helicase activity and participation in the DNA repair process. Characteristics of the HELQ protein were obtained by bioinformatics analysis, based on which the role of HELQ in DNA replication, DNA repair and maintenance of genomic stability was explored. It was concluded that modulation the function of HELQ helicase may be used in the treatment of ovarian cancer.

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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.

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