Diversity of Endonuclease V: From DNA Repair to RNA Editing

Isao Kuraoka, Isao Kuraoka

Abstract

Deamination of adenine occurs in DNA, RNA, and their precursors via a hydrolytic reaction and a nitrosative reaction. The generated deaminated products are potentially mutagenic because of their structural similarity to natural bases, which in turn leads to erroneous nucleotide pairing and subsequent disruption of cellular metabolism. Incorporation of deaminated precursors into the nucleic acid strand occurs during nucleotide synthesis by DNA and RNA polymerases or base modification by DNA- and/or RNA-editing enzymes during cellular functions. In such cases, removal of deaminated products from DNA and RNA by a nuclease might be required depending on the cellular function. One such enzyme, endonuclease V, recognizes deoxyinosine and cleaves 3' end of the damaged base in double-stranded DNA through an alternative excision repair mechanism in Escherichia coli, whereas in Homo sapiens, it recognizes and cleaves inosine in single-stranded RNA. However, to explore the role of endonuclease V in vivo, a detailed analysis of cell biology is required. Based on recent reports and developments on endonuclease V, we discuss the potential functions of endonuclease V in DNA repair and RNA metabolism.

Keywords: DNA repair; RNA editing; deamination; endonuclease V.

Figures

Figure 1
Figure 1
Formation of deoxyinosine and inosine. Deamination of adenine to hypoxanthine results in the formation of deoxyinosine in DNA and inosine in RNA. Hypoxanthine, which is recognized as guanine, pairs with cytosine. Deoxyinosine and inosine are nucleosides that form when hypoxanthine is attached to a deoxyribose ring or ribose ring, respectively.
Figure 2
Figure 2
Deoxyinosine in DNA. (A) Deoxyinosine is produced by deamination of adenine in DNA. In this case, it results in a mismatched I:T pair that requires repair; (B) Deamination of dATP to dITP leads to its incorporation into DNA by DNA polymerase during replication. When deoxyinosine is recognized as guanine, it pairs with cytosine, resulting in a non-mismatch I:C pair.
Figure 3
Figure 3
Endonuclease V in DNA repair. Deoxyinosine in DNA is repaired by alkyl-adenine DNA glycosylase (AAG) in the base excision repair (BER) pathway and by endonuclease V (EndoV) in the alternative excision repair (AER) pathway. EndoV hydrolyses the second phosphodiester bond located 3' to deoxyinosine in the DNA strand.
Figure 4
Figure 4
Inosine in RNA. (A) Inosine is produced by deamination in RNA. As inosine is recognized as guanine during translation, this deamination leads to miscoding of transcription or interference of RNA metabolism; (B) Deamination of ATP produces ITP, which accumulates in the nucleotide pool and is inserted into the transcript by RNA polymerase during transcription elongation. Transcriptional mutagenesis results in miscoding of proteins or interference of RNA metabolism; (C) Conversion of adenosine (A) residues to inosine (I) within dsRNA is catalyzed by adenosine deaminases acting on RNA (ADARs). They catalyze RNA editing at specific sites in the dsRNA structure, suggesting that their proper functioning may be crucial to RNA metabolism.
Figure 5
Figure 5
E. coli endonuclease V (eEndoV) and human endonuclease V (hEndoV) display opposing preferences in cleaving RNA and DNA. (A) 32P-labelled 30-mer ssDNA containing deoxyinosine and 21-mer ssRNA containing inosine (dI and I, respectively) were used as substrates. The positions of cleavage are indicated by arrows; (B) Activity of eEndoV (lanes 1–6) or hEndoV (lanes 7–12) when incubated with 32P-labelled DNA substrate (30-mer dI-DNA) containing deoxyinosine (lanes 1–2 and lanes 7–8) or 32P-labelled RNA substrate (21-mer I-RNA) containing inosine (lanes 3–4 and lanes 9–10) or both DNA and RNA substrates (lanes 5–6 and lanes 11–12) at 37 °C for 30 min. The cleavage products (15-mer dI-DNA and 12-mer I-RNA) are indicated by denaturing polyacrylamide gel analysis.
Figure 6
Figure 6
Human endonuclease V in RNA editing. Inosine in RNA is produced by ADARs or inosine monophosphate (IMP). Human endonuclease V can cleave the second phosphodiester bond located at 3' end of inosine in the RNA strand. Endo- or exo ribonuclease will further digest the cleaved RNA.

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