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Silencing of viral genomes by SMC5/6 is a three-step process

SUMMARY

In addition to its role in chromosome maintenance, the six-membered Smc5/6 complex functions as a restriction factor that binds to and transcriptionally silences viral and other episomal DNA. However, the underlying mechanism is unknown. In this study, led by GCIR member Professor Michel Strubin and Drs Fabien Abdul and Aurélie Diman, the authors show that transcriptional silencing by the human Smc5/6 complex is a three-step process. The first step is entrapment of the episomal DNA by a mechanism dependent on Smc5/6 ATPase activity and a function of its Nse4a subunit for which the Nse4b paralog cannot substitute. The second step results in Smc5/6 recruitment to promyelocytic leukemia nuclear bodies by SLF2 (the human ortholog of Nse6). The third step promotes silencing through a mechanism requiring Nse2 but not its SUMO ligase activity. By contrast, the related cohesin and condensin complexes fail to bind to or silence episomal DNA, indicating a property unique to Smc5/6.

This work was supported by grants from the Swiss National Science Foundation, by the Canton of Geneva and by Gilead Sciences.

Full article: https://www.nature.com/articles/s41594-022-00829-0

Why is this article important?

The protein complex Smc5/6 is essential for chromosome maintenance and functions as a host restriction factor against hepatitis B virus (HBV). Specifically, Smc5/6 binds to the circular genome of HBV DNA, thereby blocking viral transcription. HBV antagonises this restriction by expressing the regulatory protein HBx, which targets Smc5/6 for proteasomal degradation. Smc5/6 restriction is conserved in mammals and is not restricted to the HBV genome. It functions as a broad-acting restriction factor that selectively operates on extrachromosomal DNA templates to silence HBV and potentially other clinically important DNA viruses. How Smc5/6 detects and preferentially binds to episomal DNA and how it restricts gene transcription is not yet known.

The authors of this article, led by GCIR member Professor Michel Strubin, performed a structure-function analysis of Smc5/6 to identify the enzymatic activities and structural properties involved in its restriction function. In particular, they tested mutants and isoforms for their ability to promote episomal silencing using a functional complementation assay. They also explored whether the other SMC family members, cohesin and condensin, exhibit similar restriction activities. Their results reveal that episomal restriction is unique to Smc5/6. Furthermore, they demonstrate that silencing is a three-step process involving binding of Smc5/6 to DNA, recruitment to promyelocytic leukaemia nuclear bodies by SLF2 and silencing by a mechanism involving a novel function of Nse2. They also provide new information on how and under what circumstances the HBx protein interacts with Smc5/6, which may have therapeutic implications.

 UNIGE Press Release

20 Sept 2022

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