Kiwon Park

All Publications

• Human immunodeficiency virus-1 induces host genomic R-loops and preferentially integrates its genome near the R-loop regions. eLife Park, K., Lee, D., Jeong, J., Lee, S., Kim, S., Ahn, K. 2024; 13

  Abstract

  Although HIV-1 integration sites favor active transcription units in the human genome, high-resolution analysis of individual HIV-1 integration sites has shown that the virus can integrate into a variety of host genomic locations, including non-genic regions. The invisible infection by HIV-1 integrating into non-genic regions, challenging the traditional understanding of HIV-1 integration site selection, is more problematic because they are selected for preservation in the host genome during prolonged antiretroviral therapies. Here, we showed that HIV-1 integrates its viral genome into the vicinity of R-loops, a genomic structure composed of DNA-RNA hybrids. VSV-G-pseudotyped HIV-1 infection initiates the formation of R-loops in both genic and non-genic regions of the host genome and preferentially integrates into R-loop-rich regions. Using a HeLa cell model that can independently control transcriptional activity and R-loop formation, we demonstrated that the exogenous formation of R-loops directs HIV-1 integration-targeting sites. We also found that HIV-1 integrase proteins physically bind to the host genomic R-loops. These findings provide novel insights into the mechanisms underlying retroviral integration and the new strategies for antiretroviral therapy against HIV-1 latent infection.

  View details for DOI 10.7554/eLife.97348

  View details for PubMedID 39630854

  View details for PubMedCentralID PMC11616997

• Human cytomegalovirus harnesses host L1 retrotransposon for efficient replication. Nature communications Hwang, S. Y., Kim, H., Denisko, D., Zhao, B., Lee, D., Jeong, J., Kim, J., Park, K., Park, J., Jeong, D., Park, S., Choi, H. J., Kim, S., Lee, E. A., Ahn, K. 2024; 15 (1): 7640

  Abstract

  Genetic parasites, including viruses and transposons, exploit components from the host for their own replication. However, little is known about virus-transposon interactions within host cells. Here, we discover a strategy where human cytomegalovirus (HCMV) hijacks L1 retrotransposon encoded protein during its replication cycle. HCMV infection upregulates L1 expression by enhancing both the expression of L1-activating transcription factors, YY1 and RUNX3, and the chromatin accessibility of L1 promoter regions. Increased L1 expression, in turn, promotes HCMV replicative fitness. Affinity proteomics reveals UL44, HCMV DNA polymerase subunit, as the most abundant viral binding protein of the L1 ribonucleoprotein (RNP) complex. UL44 directly interacts with L1 ORF2p, inducing DNA damage responses in replicating HCMV compartments. While increased L1-induced mutagenesis is not observed in HCMV for genetic adaptation, the interplay between UL44 and ORF2p accelerates viral DNA replication by alleviating replication stress. Our findings shed light on how HCMV exploits host retrotransposons for enhanced viral fitness.

  View details for DOI 10.1038/s41467-024-51961-y

  View details for PubMedID 39223139

  View details for PubMedCentralID PMC11369119

• STING facilitates nuclear import of herpesvirus genome during infection. Proceedings of the National Academy of Sciences of the United States of America Hong, Y., Jeong, H., Park, K., Lee, S., Shim, J. Y., Kim, H., Song, Y., Park, S., Park, H. Y., Kim, V. N., Ahn, K. 2021; 118 (33)

  Abstract

  Once inside the host cell, DNA viruses must overcome the physical barrier posed by the nuclear envelope to establish a successful infection. The mechanism underlying this process remains unclear. Here, we show that the herpesvirus exploits the immune adaptor stimulator of interferon genes (STING) to facilitate nuclear import of the viral genome. Following the entry of the viral capsid into the cell, STING binds the viral capsid, mediates capsid docking to the nuclear pore complex via physical interaction, and subsequently enables accumulation of the viral genome in the nucleus. Silencing STING in human cytomegalovirus (HCMV)-susceptible cells inhibited nuclear import of the viral genome and reduced the ensuing viral gene expression. Overexpressing STING increased the host cell's susceptibility to HCMV and herpes simplex virus 1 by improving the nuclear delivery of viral DNA at the early stage of infection. These observations suggest that the proviral activity of STING is conserved and exploited by the herpesvirus family. Intriguingly, in monocytes, which act as latent reservoirs of HCMV, STING deficiency negatively regulated the establishment of HCMV latency and reactivation. Our findings identify STING as a proviral host factor regulating latency and reactivation of herpesviruses.

  View details for DOI 10.1073/pnas.2108631118

  View details for PubMedID 34385328

  View details for PubMedCentralID PMC8379909

• Aicardi-Goutières syndrome-associated gene SAMHD1 preserves genome integrity by preventing R-loop formation at transcription-replication conflict regions. PLoS genetics Park, K., Ryoo, J., Jeong, H., Kim, M., Lee, S., Hwang, S. Y., Ahn, J., Kim, D., Moon, H. C., Baek, D., Kim, K., Park, H. Y., Ahn, K. 2021; 17 (4): e1009523

  Abstract

  The comorbid association of autoimmune diseases with cancers has been a major obstacle to successful anti-cancer treatment. Cancer survival rate decreases significantly in patients with preexisting autoimmunity. However, to date, the molecular and cellular profiles of such comorbidities are poorly understood. We used Aicardi-Goutières syndrome (AGS) as a model autoimmune disease and explored the underlying mechanisms of genome instability in AGS-associated-gene-deficient patient cells. We found that R-loops are highly enriched at transcription-replication conflict regions of the genome in fibroblast of patients bearing SAMHD1 mutation, which is the AGS-associated-gene mutation most frequently reported with tumor and malignancies. In SAMHD1-depleted cells, R-loops accumulated with the concomitant activation of DNA damage responses. Removal of R-loops in SAMHD1 deficiency reduced cellular responses to genome instability. Furthermore, downregulation of SAMHD1 expression is associated with various types of cancer and poor survival rate. Our findings suggest that SAMHD1 functions as a tumor suppressor by resolving R-loops, and thus, SAMHD1 and R-loop may be novel diagnostic markers and targets for patient stratification in anti-cancer therapy.

  View details for DOI 10.1371/journal.pgen.1009523

  View details for PubMedID 33857133

  View details for PubMedCentralID PMC8078737

• L1 retrotransposons exploit RNA m6A modification as an evolutionary driving force. Nature communications Hwang, S. Y., Jung, H., Mun, S., Lee, S., Park, K., Baek, S. C., Moon, H. C., Kim, H., Kim, B., Choi, Y., Go, Y. H., Tang, W., Choi, J., Choi, J. K., Cha, H. J., Park, H. Y., Liang, P., Kim, V. N., Han, K., Ahn, K. 2021; 12 (1): 880

  Abstract

  L1 retrotransposons can pose a threat to genome integrity. The host has evolved to restrict L1 replication. However, mechanisms underlying L1 propagation out of the host surveillance remains unclear. Here, we propose an evolutionary survival strategy of L1, which exploits RNA m6A modification. We discover that m6A 'writer' METTL3 facilitates L1 retrotransposition, whereas m6A 'eraser' ALKBH5 suppresses it. The essential m6A cluster that is located on L1 5' UTR serves as a docking site for eukaryotic initiation factor 3 (eIF3), enhances translational efficiency and promotes the formation of L1 ribonucleoprotein. Furthermore, through the comparative analysis of human- and primate-specific L1 lineages, we find that the most functional m6A motif-containing L1s have been positively selected and became a distinctive feature of evolutionarily young L1s. Thus, our findings demonstrate that L1 retrotransposons hijack the RNA m6A modification system for their successful replication.

  View details for DOI 10.1038/s41467-021-21197-1

  View details for PubMedID 33563981

  View details for PubMedCentralID PMC7873242

• A central role for PI3K-AKT signaling pathway in linking SAMHD1-deficiency to the type I interferon signature. Scientific reports Oh, C., Ryoo, J., Park, K., Kim, B., Daly, M. B., Cho, D., Ahn, K. 2018; 8 (1): 84

  Abstract

  The autoimmune disorder Aicardi-Goutières syndrome (AGS) is characterized by a constitutive type I interferon response. SAMHD1 possesses both dNTPase and RNase activities and mutations in SAMHD1 cause AGS; however, how SAMHD1-deficiency causes the type I interferon response in patients with AGS remains unknown. Here, we show that endogenous RNA substrates accumulated in the absence of SAMHD1 act as a major immunogenic source for the type I interferon response. Reconstitution of SAMHD1-negative human cells with wild-type but not RNase-defective SAMHD1 abolishes spontaneous type I interferon induction. We further identify that the PI3K/AKT/IRF3 signaling pathway is essential for the type I interferon response in SAMHD1-deficient human monocytic cells. Treatment of PI3K or AKT inhibitors dramatically reduces the type I interferon signatures in SAMHD1-deficient cells. Moreover, SAMHD1/AKT1 double knockout relieves the type I interferon signatures to the levels observed for wild-type cells. Identification of AGS-related RNA sensing pathway provides critical insights into the molecular pathogenesis of the type I interferonopathies such as AGS and overlapping autoimmune disorders.

  View details for DOI 10.1038/s41598-017-18308-8

  View details for PubMedID 29311560

  View details for PubMedCentralID PMC5758801