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SARS-CoV-2 Research - ORF6 And NSP13 Proteins Cause Degradation Of The DNA Damage Response Kinase  Mar 15, 2023  9 days ago
SARS-CoV-2 Research: ORF6 And NSP13 Proteins Cause Degradation Of The DNA Damage Response Kinase CHK1 Through Proteasome And Autophagy
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SARS-CoV-2 Research: ORF6 And NSP13 Proteins Cause Degradation Of The DNA Damage Response Kinase CHK1 Through Proteasome And Autophagy
SARS-CoV-2 Research - ORF6 And NSP13 Proteins Cause Degradation Of The DNA Damage Response Kinase  Mar 15, 2023  9 days ago
SARS-CoV-2 Research: A new study by Italian researchers have found that the SARS-Cov-2 ORF6 and NSP13 proteins cause degradation of the DNA Damage Response or DDR involving the kinase CHK1 through proteasome and Autophagy.

The study team comprised of researchers from:
-IFOM ETS - The AIRC Institute of Molecular Oncology, Milan, Italy
-International Centre for Genetic Engineering and Biotechnology, Trieste, Italy
-University of Palermo, Palermo, Italy
-IRCCS San Raffaele Scientific Institute, Italy
-University, Milan, Italy
-University of Padova, Padova, Italy
-Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
-Cogentech Società Benefit srl, Milan, Italy
Although SARS-CoV-2 was reported to alter several cellular pathways, its impact on DNA integrity and the mechanisms involved remain unknown.
The SARS-CoV-2 Research team showed that SARS-CoV-2 causes DNA damage and elicits an altered DNA damage response. Mechanistically, SARS-CoV-2 proteins ORF6 and NSP13 cause degradation of the DNA damage response kinase CHK1 through proteasome and autophagy, respectively.
CHK1 loss leads to deoxynucleoside triphosphate (dNTP) shortage, causing impaired S-phase progression, DNA damage, pro-inflammatory pathways activation and cellular senescence.
Interestingly, the study found that supplementation of deoxynucleosides reduces that.
Also, it was found that SARS-CoV-2 N-protein impairs 53BP1 focal recruitment by interfering with damage-induced long non-coding RNAs, thus reducing DNA repair.
The same key observations are recapitulated in SARS-CoV-2-infected mice and patients with COVID-19.
The study findings show that SARS-CoV-2, by boosting ribonucleoside triphosphate levels to promote its replication at the expense of dNTPs and by hijacking damage-induced long non-coding RNAs’ biology, threatens genome integrity and causes altered DNA damage response activation, induction of inflammation and cellular senescence.
In conclusion, the study showed that SARS-CoV-2 infection induces DNA damage, through CHK1 degradation and impaired 53BP1 recruitment, and cellular senescence.
The study findings were published in the peer reviewed journal: Nature Cell Biology.
It should be noted that viral infections can impact on several cellular pathways, including the autophagy pathway, the ubiquitin–proteasome system (UPS) and the DNA damage response (DDR).
Though the interplay between some DNA viruses and DDR has been studied, much less is known about RNA viruses.
While SARS-CoV-2 infection has been suggested to engage components of the DDR machinery, a thorough characterization and a mechanistic probing of the impact of SARS-CoV-2 on genome integrity and DDR engagement is lacking.
The DNA Damage Response or DDR is a network of pathways that sense DNA lesions, signal their presence and coordinate their repair.
The study findings showed that SARS-CoV-2 infection causes DNA damage, as observed in two immortal cell lines, in primary human cells and in vivo in mice and humans.
The study team identified at least two mechanisms responsible for DNA damage accumulation: one impacting on cellular dNTP metabolism leading to DNA replication impairment; another impeding 53BP1 activation and reducing DNA repair.
Interestingly, the DNA damage accumulated triggers DDR activation, but in an altered way.
It was found for instance that CHK1, together with P53, decreases following SARS-CoV-2 infection.
Degradation of DDR factors is a strategy shared by different viruses to override host defenses.
CHK1 is known to control the expression of E2F transcription factors, important regulators of cell-cycle progression and consequently of the RRM2 gene, allowing DNA synthesis in S-phase.
The study findings demonstrated that SARS-CoV-2 infection leads to CHK1 loss and consequent RRM2 decrease, causing dNTP shortage and prolonged S-phase, consistent with the generation of DNA replication stress and DNA damage. This cascade of events leads to the establishment of cellular senescence and activation of pro-inflammatory pathways.
It was also noted that CHK1 depletion is sufficient to recapitulate RRM2 reduction, DNA damage accumulation and cytokine expression.
Importantly, the administration of deoxynucleosides or dNs to SARS-CoV-2-infected cells reduced virally induced DNA damage, DDR activation and cytokine expression, thus demonstrating the causative role of dNTP depletion in these events.
The study team proposes that this is probably the unmeant consequence of the dire need for rNTPs of SARS-CoV-2. Staggering two-thirds of total RNA in SARS-CoV-2-infected cells is of viral origin: thus infected cells need to triple their normal RNA synthesis capacity. Therefore, the virus has been under evolutionary pressure to boost rNTP levels. One way is to reduce CHK1 levels, causing decreased RRM2 activity and consequent accumulation of rNTPs at the expense of dNTPs.
It was also found that at least two SARS-CoV-2 proteins cause CHK1 degradation. ORF6, by associating with the nuclear pore complex, interferes with CHK1 nuclear import, leading to CHK1 cytoplasmic mis-localization and consequent proteasomal degradation. Notably, a point mutation that disrupts ORF6 binding to the nuclear pore complex prevented CHK1 poly-ubiquitination, degradation and DNA damage accumulation.
Importantly, proteasome inhibition with MG132 in ORF6-expressing cells was sufficient to rescue CHK1 levels. Differently, NSP13 leads to CHK1 depletion through the autophagic route, as indicated by the recovery of CHK1 levels upon treatment with autophagy inhibitors or with RNAi against key autophagy factors.
Besides the ability induce DNA damage, SARS-CoV-2 inhibits its repair.
The study team observed a strikingly reduced ability of 53BP1 to form DDR foci, despite unaltered protein levels, in infected cells.
The study findings propose that SARS-CoV-2 N, an avid RNA-binding protein, impairs 53BP1 condensation at DSB by competing for dilncRNA binding.
Indeed, both 53BP1 and N-protein undergo LLPS in an RNA-dependent manner, and the study findings demonstrate that N-protein, just like 53BP1, binds to dilncRNA.
The study findings suggest a nuclear role of SARS-CoV-2 N-protein. Although both SARS-CoV and SARS-CoV-2 N-proteins bear functional nuclear localization signals, they are only partly nuclear, but phylogenetic studies have correlated the enhancement of motifs that promote nuclear localization of viral N-proteins with coronavirus pathogenicity and virulence.
Hyperactivation of inflammatory pathways is responsible for fatal COVID-19 cases. DNA damage accumulation and chronic DDR activation are potent inducers of inflammation.
SARS-CoV-2 infection of cultured cells activates multiple pro-inflammatory signaling pathways, including cGAS/STING, STAT1 and p38/MAPK, similar to CHK1 depletion.
The study team, supported by reports that disruption of the CHK1–RRM2 pathway triggers cellular senescence and their own evidence, propose that SARS-CoV-2-mediated CHK1 loss promotes a pro-inflammatory programme akin to the senescence-associated secretory phenotype.
The study team observed that SARS-CoV-2 infection causes DNA damage accumulation that correlates with markers of cellular senescence, in primary cells and in vivo.
 In particular, infected pneumocytes express high p21 levels, while polymorphonuclear and monocytoid inflammatory elements have elevated p16 reminiscent of a two-wave model of inflammatory response: an initial cell-intrinsic one and a second one triggered by the immune system.
The study findings indicate that SARS-CoV-2-induced DNA damage triggers a cell-intrinsic pro-inflammatory programme that, in concert with the immune response, fuels the strong inflammatory response observed in patients with COVID-19.
By proposing a mechanism for the generation of DNA damage and the activation of DDR pathways and of a pro-inflammatory programme, the study findings provide a model to improve the understanding of SARS-CoV-2-induced cellular senescence.
The study team added that in this regard, it will also be interesting to determine if persistent DNA damage and DDR activation, features of cellular senescence, following SARS-CoV-2 infection, contribute to the chronic manifestations of the pathology known as long COVID.
For the latest SARS-CoV-2 Research, keep on logging to Thailand Medical News.


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