Protein phosphatase magnesium-dependent 1 delta (PPM1D) terminates the cell cycle checkpoint by dephosphorylating the tumour suppressor protein p53. By targeting additional substrates at chromatin, PPM1D contributes to the control of DNA damage response and DNA repair. Using proximity biotinylation followed by proteomic analysis, we identified a novel interaction between PPM1D and the shelterin complex that protects telomeric DNA. In addition, confocal microscopy revealed that endogenous PPM1D localises at telomeres. Further, we found that ATR phosphorylated TRF2 at S410 after induction of DNA double strand breaks at telomeres and this modification increased after inhibition or loss of PPM1D. TRF2 phosphorylation stimulated its interaction with TIN2 both in vitro and at telomeres. Conversely, induced expression of PPM1D impaired localisation of TIN2 and TPP1 at telomeres. Finally, recruitment of the DNA repair factor 53BP1 to the telomeric breaks was strongly reduced after inhibition of PPM1D and was rescued by the expression of TRF2-S410A mutant. Our results suggest that TRF2 phosphorylation promotes the association of TIN2 within the shelterin complex and regulates DNA repair at telomeres.

• MeSH
• Phosphorylation MeSH
• Humans MeSH
• DNA Damage MeSH
• Telomeric Repeat Binding Protein 2 * MeSH
• Telomere-Binding Proteins * metabolism   MeSH
• Proteomics MeSH
• Shelterin Complex * MeSH
• Telomere metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Telomeric Repeat Binding Protein 2 * MeSH
• Telomere-Binding Proteins * MeSH
• Shelterin Complex * MeSH
• TINF2 protein, human MeSH Browser

Transcription is often the first biosynthetic event of viral infection. Viruses produce preferentially viral transcriptional regulators (vTRs) essential for expressing viral genes and regulating essential host cell proteins to enable viral genome replication. As vTRs are unique viral proteins that promote the transcription of viral nucleic acid, vTRs interact with host proteins to suppress detection and immune reactions to viral infection. Thus, vTRs are promising therapeutic targets that are sequentially and structurally distinct from host cell proteins. Here, we review vTRs of three human oncoviruses: HBx of hepatitis B virus, HBZ of human T-lymphotropic virus type 1, and Rta of Epstein-Barr virus. We present three cunningly exciting and dangerous transcription strategies that make viral infections so efficient. We use available structural and functional knowledge to critically examine the potential of vTRs as new antiviral-anticancer therapy targets. For each oncovirus, we describe (i) the strategy of viral genome transcription; (ii) vTRs' structure and binding partners essential for transcription regulation; and (iii) advantages and challenges of vTR targeting in antiviral therapies. We discuss the implications of vTR regulation for oncogenesis and perspectives on developing novel antiviral and anticancer strategies.

• Publication type
• Journal Article MeSH

The repetitive telomeric DNA at chromosome ends is protected from unwanted repair by telomere-associated proteins, which form the shelterin complex in mammals. Recent works have provided new insights into the mechanisms of how human shelterin assembles and recruits telomerase to telomeres. Inhibition of telomerase activity and telomerase recruitment to chromosome ends is a promising target for anticancer therapy. Here, we summarize results of quantitative assessments and newly emerged structural information along with the status of the most promising approaches to telomerase inhibition in cancer cells. We focus on the mechanism of shelterin assembly and the mechanisms of how shelterin affects telomerase recruitment to telomeres, addressing the conceptual dilemma of how shelterin allows telomerase action and regulates other essential processes. We evaluate how the identified critical interactions of telomerase and shelterin might be elucidated in future research of new anticancer strategies.

• Keywords
• anticancer, assembly, inhibitor, protein-DNA interaction, protein-protein interaction, quantitative biology, shelterin, telomerase, telomere,
• MeSH
• Enzyme Inhibitors pharmacology   MeSH
• Humans MeSH
• Telomere-Binding Proteins chemistry   metabolism   MeSH
• Antineoplastic Agents pharmacology   MeSH
• Shelterin Complex MeSH
• Telomerase antagonists & inhibitors   chemistry   metabolism   MeSH
• Protein Binding MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Enzyme Inhibitors MeSH
• Telomere-Binding Proteins MeSH
• Antineoplastic Agents MeSH
• Shelterin Complex MeSH
• Telomerase MeSH