Signal interfering DNA (siDNA) is a class of short modified double stranded DNA molecules, 8–64 base pairs in length. siDNA molecules are capable of inhibiting

DNA repair DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...

activities by interfering with multiple repair pathways. These molecules are known to act by mimicking DNA breaks and interfering with recognition and repair of DNA damage induced on chromosomes by irradiation or genotoxic products.

''Dbait''

''Dbait'' is a specific siDNA molecule that has been shown to mimic signalling of double-stranded DNA breaks (DSBs) ''in vivo''. Currently, ''Dbait'' is the only type of siDNA molecule having been reviewed.

Mechanism of Action of ''Dbait''

The siDNA family, led by ''Dbait,'' consists of 32 base pairs

deoxyribonucleotide A deoxyribonucleotide is a nucleotide that contains deoxyribose. They are the monomeric units of the informational biopolymer, deoxyribonucleic acid ( DNA). Each deoxyribonucleotide comprises three parts: a deoxyribose sugar (monosaccharide), a nit ...

forming an intramolecular double helix, which mimicks DNA double-strand break lesions. In the event of a double-stranded break in the genome, the cell most commonly repairs the damaged segment via non-homologous end joining (NHEJ). NHEJ involves the ligation of the damaged segments without using a homologous strand as a template, and can lead to frameshift mutations and failure of the cell to properly halt the cell division cycle, which could lead to the cancerization of the cell. Dbait functions primarily by targeting the NHEJ pathway, with the cell detecting the presence of siDNA molecules as double stranded breaks (DSBs). Dbait triggers baited activation of signalling enzymes involved in NHEJ-mediated genome repair to initiate the appropriate cellular response. Dbait is first bound to by Ku protein complexes that trigger the phosphorylation of NHEJ initiation factors such as DNA-PK (DNA-dependent protein kinase) and PARP (polyadenyl-ribose polymerase). DNA-PK overactivation through Dbait in turn triggers the activity of numerous signalling proteins in the NHEJ signalling cascade. DNA-PK hyperactivation induces pan-nuclear phosphorylation of histone

H2AX H2A histone family member X (usually abbreviated as H2AX) is a type of histone protein from the H2A family encoded by the ''H2AFX'' gene. An important phosphorylated form is γH2AX (S139), which forms when double-strand breaks appear. In humans ...

among all the

chromatin Chromatin is a complex of DNA and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in r ...

. H2AX phosphorylation is the signal, which allows double-strand break repair proteins to form DNA repair complexes selectively on DNA double-strand breaks. Dbait-dependent unspecific phosphorylation of H2AX results in inefficient double strand break recognition and repair.

Possible therapeutic application of Dbait

Most anti-cancer therapies act by induction of

DNA damage DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA d ...

(

chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothe ...

and

radiation therapy Radiation therapy or radiotherapy, often abbreviated RT, RTx, or XRT, is a therapy using ionizing radiation, generally provided as part of cancer treatment to control or kill malignant cells and normally delivered by a linear accelerator. Radi ...

). DNA breaks are the most lethal damage for cells, as double-stranded breaks can lead to loss of entire chromosomal fragments, and even one single double-strand break if unrepaired is sufficient to lead to cell death. ''Dbait'' enhances the efficacy of the DNA damaging agents as demonstrated with radiation therapy and/or chemotherapy in multiple ''in vivo'' experimental models such as melanoma,

glioblastoma Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality ...

and colorectal cancer. Preclinical proof of concept of the synergic effect of the clinical candidate, ''DT01'', with radiation therapy lead to a first-in-human Phase I, to evaluate the tolerance and efficacy of local ''DT01'' administration in association with RT in patients suffering from in-transit metastases of melanoma. Encouraging results were published in May 2016.

References

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