Key Points
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Helicase-dependent DNA damage response and repair mechanisms help cells to cope with endogenous or exogenous stress to prevent chromosomal instability and maintain cellular homeostasis.
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Inactivating mutations in DNA helicase genes are linked to genetic disorders that are frequently associated with various cancers. However, the expression of many DNA helicases is upregulated in transformed or neoplastic cells and tissues and is required for cancer cell proliferation or resistance to DNA damage imposed by chemotherapies.
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The RecQ and iron-sulphur (Fe-S) families of DNA helicases have prominent roles in the maintenance of genomic stability through their catalytic functions and protein interactions in telomere maintenance and DNA repair pathways including nucleotide-excision repair (NER), homologous recombination (HR)-mediated repair of double-strand breaks (DSBs), interstrand crosslink (ICL) repair, and base-excision repair (BER).
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Specialized DNA helicases efficiently unwind G-quadruplex (G4) DNA and other forms of alternative DNA structures such as telomeric displacement loops (T-loops). Emerging evidence suggests that DNA helicases that unwind non-conventional DNA structures have important roles in the replication or repair of telomeres.
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Replication forks in rapidly dividing cancer cells are likely to encounter DNA lesions that perturb fork progression. Evidence suggests that certain DNA helicases help cells to cope with replicative lesions by remodelling the fork, restoring the integrity of broken replication forks, or having a role in the signalling mechanism for the intra-S-phase checkpoint.
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Elevated expression of DNA helicases in rapidly proliferating cells and tumours suggests that they have a role in resistance to DNA-damaging agents and may represent good biomarkers for response to chemotherapies.
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High-throughput screening of chemical libraries may prove to be beneficial for the discovery of small molecules that modulate helicase function in vivo. Such compounds may be useful in synthetic lethal approaches used in anticancer strategies that target tumours with existing DNA repair deficiencies.
Abstract
Helicases have major roles in genome maintenance by unwinding structured nucleic acids. Their prominence is marked by various cancers and genetic disorders that are linked to helicase defects. Although considerable effort has been made to understand the functions of DNA helicases that are important for genomic stability and cellular homeostasis, the complexity of the DNA damage response leaves us with unanswered questions regarding how helicase-dependent DNA repair pathways are regulated and coordinated with cell cycle checkpoints. Further studies may open the door to targeting helicases in order to improve cancer treatments based on DNA-damaging chemotherapy or radiation.
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Acknowledgements
This research was supported by the Intramural Research Program of the US National Institutes of Health (NIH), National Institute on Aging (NIA). I thank J. Burril of the NIA Visual Media Section for artwork in drafts of figures 2,3 and 5. I express gratitude to M. Seidman, Y. Liu, V. Bohr and W. Wang (NIA-NIH) for critically reading the manuscript, and S. Matson (University of North Carolina at Chapel Hill) for introducing me to the helicase field and for providing strong mentorship. I apologize to those researchers whose published work on DNA helicases was not cited owing to length restrictions.
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Glossary
- Poikiloderma
-
A skin condition that consists of areas of increased and decreased pigmentation, prominent blood vessels and thinning of the skin.
- Homologous recombination
-
(HR). A type of genetic recombination in which nucleotide sequences are exchanged between two similar or identical molecules of DNA. HR is most widely used by cells to accurately repair damage that involves both strands, such as double-strand breaks or interstrand DNA crosslinks.
- Base-excision repair
-
(BER). A DNA repair pathway that operates on small DNA lesions such as oxidized or reduced bases, fragmented or non-bulky adducts, or those produced by methylating agents. The resulting single-strand break can be processed by either short-patch BER (through which a single nucleotide is replaced) or long-patch BER (through which 2–10 new nucleotides are synthesized).
- Transcription Factor IIH
-
(TFIIH). A general transcription factor complex composed of multiple protein subunits that enables formation of the RNA polymerase II pre-initiation complex. TFIIH is also implicated in nucleotide-excision repair (NER).
- Nucleotide-excision repair
-
(NER). This pathway recognizes bulky distortions in the DNA that occur after ultraviolet radiation or chemotherapy. Recognition of these distortions leads to the removal of a short single-stranded DNA segment that includes the lesion, creating a single-strand gap in the DNA, which is subsequently filled by a DNA polymerase.
- G-quadruplex
-
(G4). A four-stranded nucleic acid structure stabilized by non-Watson–Crick Hoogsteen base-pairing within stacks of four planar-orientated guanosine nucleotides. G-quadruplex structures can form within or between G-rich strands of telomeric DNA or other G-rich sequences.
- Intra-S-phase checkpoint
-
Single-stranded DNA created at the stalled replication fork generates a signal mediated by phosphorylation of target proteins (for example, mammalian ATR) that prevents the cell cycle from progressing to the G2 phase until replication is complete.
- DNA charge transport
-
The process of transporting electrons along the axis of a double helical DNA molecule through the overlapping π-orbitals of stacked DNA base pairs.
- Slippage
-
When a helicase loses its firm grasp on single-stranded DNA, causing it to slide backwards owing to re-annealing of complementary strands at the DNA fork.
- Translesion synthesis
-
A DNA damage tolerance process that allows replication past DNA lesions. If the normal replicative polymerase cannot insert a base owing to damage in the template strand, it is often replaced by a lower-fidelity translesion polymerase.
- Non-homologous end-joining
-
(NHEJ). Unlike homologous recombination-mediated repair, NHEJ rejoins broken ends of DNA following double-strand breaks without using a homologous DNA template and can therefore be accompanied by loss of nucleotides and errors.
- Mismatch repair
-
(MMR). A process that acts during DNA replication to correct base pairing errors made by the DNA polymerases.
- RAD51–double-stranded DNA filaments
-
During an early stage of homologous recombination, the major eukaryotic recombinase RAD51 forms nucleoprotein filaments on double-stranded DNA to initiate the homology search and exchange of DNA strands. Filaments can also occur on single-stranded DNA.
- Synthetic lethality
-
Cell death resulting from the combined inactivation or inhibition of two genes or gene products that are non-lethal when inactivated individually. Synthetic lethality can occur between genes and small molecules, which may lead to anticancer therapies.
- Sister-chromatid exchange
-
(SCE). A crossing-over event between sister chromatids, leading to the exchange of homologous stretches of DNA sequence.
- G4 ligand
-
A typically planar aromatic small molecule that preferentially binds G-quadruplex (G4) DNA with high affinity. There are also proteins that preferentially bind G4 DNA.
- Shelterin complex
-
A six-protein complex that localizes to the terminal TTAGGG repeats of mammalian chromosome ends, enabling cells to distinguish their natural chromosome ends from DNA breaks. The shelterin complex represses DNA repair reactions and regulates telomerase-based telomere maintenance.
- T-loops
-
The 3′ single-stranded telomere DNA overhang circles around and hybridizes to the complementary strand of the adjacent double-stranded DNA to create a displacement loop (D-loop) by displacing one of the strands. T-loops are stabilized by telomere-binding proteins.
- Alternative lengthening of telomeres
-
(ALT). A recombination-based mechanism that allows telomere length maintenance in the absence of telomerase activity.
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Brosh, R. DNA helicases involved in DNA repair and their roles in cancer. Nat Rev Cancer 13, 542–558 (2013). https://doi.org/10.1038/nrc3560
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DOI: https://doi.org/10.1038/nrc3560
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