Repair of Viral Genomes by Base Excision Pathways: African Swine Fever Virus as a Paradigm

Redrejo-Rodríguez, Modesto; Rodrı́guez, Javier M.; Salas, José Valero; Salas, María

doi:10.5772/23328

Cited by 5 publications

(6 citation statements)

References 81 publications

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“…To determine the effect of D345L deletion on virus-induced IFNβ responses, the generation of D345L-deficient ASFV was attempted but failed, consistent with a previous report [ 12 ], suggesting the essential role of pD345L in ASFV replication. Conditional deletion of D345L will be attempted in further studies [ 48 , 49 ].…”

Section: Discussionmentioning

confidence: 54%

“…The pD345L protein contains an N-terminal 5’ → 3’ exonuclease domain and shows strong similarity with lambda phage exonuclease, while its C-terminal function remains unknown [ 12 ]. To investigate whether the inhibition of NF-κB activity relies on pD345L exonuclease activity, a D345L catalytic mutant (D345L-CM) was constructed (Figure 6 A).…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, ASFV encodes all BER pathway enzymes except DNA glycosylase, including AP endonuclease (pE296R), PCNA-like (pE301R); DNA polymerase X-like (pO174L); Lambda-like exonuclease (pD345L); and DNA ligase (pNP419L). It was reported that pE296R is required for ASFV growth in macrophages but not in Vero cells [ 11 ] and that pD345L is indispensable for ASFV propagation [ 12 ], suggesting an essential role of the DNA repair system in ASFV replication.…”

Section: Introductionmentioning

confidence: 99%

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ASFV pD345L protein negatively regulates NF-κB signalling by inhibiting IKK kinase activity

Chen

Wang

Gao

et al. 2022

Vet Res

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The NF-κB pathway is an essential signalling cascade in the defence against viral infections, including African swine fever virus (ASFV) infection. ASFV encodes more than 151 proteins via its own transcription machinery and possesses a great capacity to evade or subvert antiviral innate immune responses. Although some of these viral proteins have been reported, many remain unknown. Here, we show that pD345L, an ASFV-encoded lambda-like exonuclease, acts as an inhibitor of cGAS/STING-mediated NF-κB signalling by blocking the IkappaB kinase (IKKα/β) activity. Specifically, we showed that overexpression of pD345L suppresses cGAS/STING-induced IFNβ and NF-κB activation, resulting in decreased transcription of IFNβ and several proinflammatory cytokines, including IL-1α, IL-6, IL-8, and TNFα. In addition, we showed that pD345L acts at or downstream of IKK and upstream of p65. Importantly, we found that pD345L associates with the KD and HLH domains of IKKα and the LZ domain of IKKβ and thus interrupts their kinase activity towards the downstream substrate IκBα. Finally, we showed that pD345L-mediated inhibition of NF-κB signalling was independent of its exonuclease activity. Considering these results collectively, we concluded that pD345L blocks IKKα/β kinase activity via protein–protein interactions and thus disrupts cGAS/STING-mediated NF-κB signalling.

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Section: Discussionmentioning

confidence: 54%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ASFV pD345L protein negatively regulates NF-κB signalling by inhibiting IKK kinase activity

Chen

Wang

Gao

et al. 2022

Vet Res

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“… 12 However, only the base excision repair (BER) proteins—specifically, the apurinic/apyrimidinic (AP) endonuclease ( ASFV AP), the repair DNA polymerase ( ASFV PolX), and the DNA ligase ( ASFV Lig)—are involved in the correction of a damaged DNA. 13 When a damaged nucleotide base is detected, DNA glycosylase excises the damaged base and creates an abasic site. ASFV AP cleaves the sugar-phosphate bond of the abasic site, generating a break in the DNA strand and leaving a 3′-OH and a 5′-deoxyribose phosphate (5′dRP) end.…”

Section: Introductionmentioning

confidence: 99%

“…Finally, ASFV Lig seals the nick in the DNA backbone through the formation of phosphodiester bonds between 3′-OH and 5′-phosphate of adjacent nucleotides. 13 These proteins serve as the sole repair system of the virus to mitigate the oxidative damage induced by free oxygen radicals. The inhibition of these proteins could disrupt the repair process and maintenance of the ASFV, 14 leading to a damaged and non-functional genome, thereby arresting viral replication.…”

Section: Introductionmentioning

confidence: 99%

In silico identification of multi-target inhibitors from medicinal fungal metabolites against the base excision repair pathway proteins of African swine fever virus

Macalalad,

Orosco

2024

RSC Adv.

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The PHP domain of PolX from Staphylococcus aureus aids high fidelity DNA synthesis through the removal of misincorporated deoxyribo-, ribo- and oxidized nucleotides

Nagpal

Nair

2021

Sci Rep

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The X family is one of the eight families of DNA polymerases (dPols) and members of this family are known to participate in the later stages of Base Excision Repair. Many prokaryotic members of this family possess a Polymerase and Histidinol Phosphatase (PHP) domain at their C-termini. The PHP domain has been shown to possess 3′–5′ exonuclease activity and may represent the proofreading function in these dPols. PolX from Staphylococcus aureus also possesses the PHP domain at the C-terminus, and we show that this domain has an intrinsic Mn2+ dependent 3′–5′ exonuclease capable of removing misincorporated dNMPs from the primer. The misincorporation of oxidized nucleotides such as 8oxodGTP and rNTPs are known to be pro-mutagenic and can lead to genomic instability. Here, we show that the PHP domain aids DNA replication by the removal of misincorporated oxidized nucleotides and rNMPs. Overall, our study shows that the proofreading activity of the PHP domain plays a critical role in maintaining genomic integrity and stability. The exonuclease activity of this enzyme can, therefore, be the target of therapeutic intervention to combat infection by methicillin-resistant-Staphylococcus-aureus.

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Repair of Viral Genomes by Base Excision Pathways: African Swine Fever Virus as a Paradigm

Cited by 5 publications

References 81 publications

ASFV pD345L protein negatively regulates NF-κB signalling by inhibiting IKK kinase activity

ASFV pD345L protein negatively regulates NF-κB signalling by inhibiting IKK kinase activity

In silico identification of multi-target inhibitors from medicinal fungal metabolites against the base excision repair pathway proteins of African swine fever virus

The PHP domain of PolX from Staphylococcus aureus aids high fidelity DNA synthesis through the removal of misincorporated deoxyribo-, ribo- and oxidized nucleotides

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