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RNF8 Dysregulation and Down-regulation During HTLV-1 Infection Promote Genomic Instability in Adult T-Cell Leukemia
Huijun Zhi1, Xin Guo2, Yik-Khuan Ho1
1Department of Microbiology and Immunology Uniformed Services University of the Health Sciences Bethesda, MD, United States of America.
Plos Pathogens
|May 27, 2020
Summary
Human T-lymphotropic virus type 1 (HTLV-1) Tax protein hijacks RNF8 to disrupt DNA repair in adult T cell leukemia/lymphoma (ATL). This leads to genomic instability, with RNF8 downregulation selected during disease progression.
Area of Science:
- Oncology
- Virology
- Molecular Biology
- Genetics
Background:
- Genomic instability in adult T cell leukemia/lymphoma (ATL) is linked to the HTLV-1 viral oncoprotein, Tax.
- The precise mechanism by which Tax causes genomic instability is not fully understood.
- Previous work showed Tax hijacks ring finger protein 8 (RNF8), a ubiquitin E3 ligase, to activate NF-κB signaling.
Purpose of the Study:
- To investigate the role of Tax-induced RNF8 activation in DNA damage response (DDR) and genomic instability in HTLV-1 infection.
- To elucidate the mechanism by which Tax disrupts DDR signaling in infected cells.
- To examine the significance of RNF8 expression in ATL pathogenesis.
Main Methods:
- Immunofluorescence microscopy to visualize Tax-speckle structures (TSS) and co-localization of proteins.
- Analysis of DDR factor recruitment and function in HTLV-1 infected cells and Tax-expressing cells.
- Assessment of Tax mutants with altered ubiquitin assembly activity.
- Correlation of RNF8 expression levels with HTLV-1 viral load and ATL cell characteristics.
Main Results:
- HTLV-1 infected cells exhibit impaired DNA damage response (DDR).
- Tax induces nuclear "Tax-speckle structures" (TSS) that sequester DDR factors like BRCA1 and DNA-PK, dependent on RNF8.
- RNF8-dependent K63-linked polyubiquitin chains (K63-pUbs) assemble in these TSS, disrupting DDR.
- Tax mutants deficient in K63-pUb assembly show reduced TSS formation and DDR impairment.
- Loss of RNF8 expression is observed in ATL cells, correlating with reduced viral gene expression.
Conclusions:
- Tax disrupts DDR and DNA repair in HTLV-1 infected cells by hijacking RNF8 to form nuclear speckles (TSS) that sequester DDR factors.
- This Tax-mediated sequestration leads to genomic instability characteristic of ATL.
- Down-regulation of RNF8 is selected during HTLV-1 infection and ATL progression, exacerbating genomic instability.
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