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RNA polymerase reads eight-letter DNA alphabet in UC San Diego studies

RNA polymerase reads eight-letter DNA alphabet in UC San Diego studies

New Capabilities

E. coli enzyme transcribes four synthetic Hachimoji letters alongside DNA's natural four

2 days ago: ScienceDaily reports the finding

Overview

Updated 2 hours ago

All life on Earth runs on four DNA letters. Researchers at UC San Diego have shown that one of biology's core enzymes can read an eight-letter alphabet that includes four synthetic letters. The finding, published in Nature Communications, is a step toward engineered biological systems that use genetic information nature never wrote.

The work tests whether a cell's own machinery can process synthetic DNA. RNA polymerase from E. coli recognized the artificial letters through the same structural signals it uses for natural ones. That opens the door to expanded genetic systems for diagnostics, therapeutics, and data storage.

Why it matters

If expanded genetic alphabets work inside cells, scientists could build biological systems that produce compounds and functions not found in nature.

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Key Indicators

8
Letters in the Hachimoji genetic alphabet
Four natural DNA letters plus four synthetic ones.
2.42–2.75 Å
Resolution of cryo-EM structures
Four enzyme structures captured at near-atomic resolution.
~2x
Rate difference for synthetic base pairs
Synthetic pairs incorporated roughly two-fold slower than natural ones.
4
Cryo-EM structures captured
Showing RNA polymerase interacting with synthetic nucleotides.

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People Involved

Organizations Involved

Timeline

February 2019 September 2026

5 events Latest: 2 days ago
Tap a bar to jump to that date
  1. ScienceDaily reports the finding

    Latest Media

    The university's research alert is republished, drawing wider attention to the eight-letter alphabet.

  2. Hachimoji transcription study published

    Publication

    Nature Communications paper showed E. coli RNA polymerase transcribes all eight letters at near-natural rates.

  3. Hydrophobic base pair study published

    Publication

    PNAS paper showed RNA polymerase recognizes a synthetic pair without hydrogen bonds.

  4. RNA polymerase recognizes artificial base pairs

    Publication

    UC San Diego showed RNA polymerase can't distinguish synthetic AEGIS base pairs from natural ones.

  5. Hachimoji alphabet introduced

    Publication

    Benner and colleagues published the eight-letter genetic alphabet in Science, adding four synthetic nucleotides.

Historical Context

3 moments from history that rhyme with this story — and how they unfolded.

May 2014

Romesberg's semi-synthetic organism (2014)

Floyd Romesberg's lab at Scripps Research created a semi-synthetic organism with an unnatural base pair (d5SICS-dNaM) in its DNA. The bacterium E. coli replicated the synthetic pair alongside its natural DNA.

Then

The semi-synthetic organism showed that cells can replicate DNA with unnatural letters.

Now

It demonstrated the feasibility of expanded genetic systems in living cells, though the pair was later refined.

Why this matters now

Romesberg's work showed replication of unnatural letters in cells; the new study addresses transcription, the next step in gene expression.

February 2019

Hachimoji alphabet introduction (2019)

Steven Benner and colleagues published the Hachimoji eight-letter genetic alphabet in Science. The alphabet added four synthetic nucleotides to DNA's natural four, and an engineered T7 RNA polymerase could transcribe it.

Then

The alphabet was demonstrated in vitro with a simple viral enzyme.

Now

It set the stage for testing whether cellular enzymes could handle the expanded alphabet.

Why this matters now

The 2026 study answers the question the 2019 paper left open: whether a cell's own multi-subunit RNA polymerase can read all eight letters.

2000s–2020s

AEGIS six-letter system (2000s–2020s)

Benner's earlier AEGIS (Artificially Expanded Genetic Information System) added two letters to DNA's four. Six-letter AEGIS DNA aptamers carrying P and Z have been engineered to target liver cancer cells and carry chemotherapy drugs.

Then

AEGIS demonstrated practical applications of expanded alphabets in diagnostics and therapeutics.

Now

It provided the foundation for the eight-letter Hachimoji system.

Why this matters now

The new work extends AEGIS's P:Z pair to the full eight-letter alphabet and shows cellular RNA polymerase can read it.

Sources

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