Life on Earth only uses 4 DNA bases (ACGT), but in principle, there’s no good reason why we couldn’t use more. Heeding the call of “this might be possible but nature hasn’t done it yet I wonder why not?”, synthetic biologists have been tinkering with synthetic bases to see if an expanded DNA alphabet could really work. Several synthetic base pairs have been tried, and one pair was even stably maintained in a plasmid by E. coli.
However, some of these synthetic base pairs mess with the DNA structure a bit, introducing bumps and bends. To play well with the whole range of enzymes DNA needs to interact with, it might be best for synthetic bases to form the same double-helical structure as regular DNA.
A recent pair of papers demonstrated for the first time that Z:P base pairs form the canonical DNA structure, and that the expanded DNA sequence space can hold useful new functions.
Z:P Pairs Nicely with Standard DNA Structure
In the first paper, headed by Millie Georgiadis, the team crystallized DNA sequences with Z:P pairs, and found:
- Z:P pairs form the usual Watson-Crick structure, even with a stretch of 6 Z:Ps in a row.
- DNA with Z:P forms the standard double helix (actually, both the A- and B-forms of the standard double helix).
- Z:P does shift DNA’s major groove around a bit, which could help expand its range of functions.
Evolution of Z:P DNA for New Function
In the second paper, led by Liqin Zhang and Zunyi Yang, the team searched the expanded sequence space of ATGCZP DNA for new functions. Specifically, they used PCR-based, in vitro evolution to select for 25-mer sequences that would specifically bind to liver cancer cells but not to a benign control line. Not only did Z:P pairs survive ~200 cycles of PCR, but most of the top cancer-binding sequences contained at least one Z:P.
P.S., Because we know you’re curious…
Z: stands for 6-amino-5-nitro-3-(1′-β-D-2′-deoxyribofuranosyl)-2(1H)-pyridone, which, curiously, does not contain a Z, and
P: stands for 2-amino-8-(1′-β-d-2′-deoxyribofuranosyl)-imidazo[1,2-a]-1,3,5-triazin-4(8H)-one), which, curiously, does not contain a P.