Key words:
mutagenesis; cytidine deaminase fusion; synthetic biology; T7
promoter; Saccharomyces cerevisiae
Introduction
Mutations can increase genome diversity and drive the evolution of
organisms. Random mutagenesis plays a crucial role in industrial strain
breeding, new drug research and development, protein engineering and
many other aspects.[1-6] However, under natural
conditions, the genomic error rate is as low as
10-8~10-9, which
makes natural evolution a very slow process. Therefore, how to increase
the mutation rate of target genes, expand the mutation spectrum, and
obtain the mutants with desired phenotypes efficiently are the essential
problems that researchers have to consider.
There has been a lot of research into accelerating the evolution over
the last few decades. Several strategies have been employed by
researchers to accelerate the evolution of target genes, resulting in
impressive progress. Radiation or chemically-induced mutagenesis is a
conventional and commonly-used strategy to generate random
mutations.[7-9] This method effectively increases
the mutation rate of the target gene and is relatively straightforward
to implement. As CRISPR/Cas techniques continue to advance, a multitude
of CRISPR-based targeted mutagenesis systems have emerged, including
CHAnGE, MAGESTIC, and many others.[10-13] In these
systems, Cas9 variants are capable of precisely identifying the targeted
gene, while gRNAs facilitate accurate and traceable editing of the gene.
This leads to the production of numerous mutants with varying genotypes.
By using CRISPR-based targeting systems, mutations in non-targeted
regions are avoided. Additionally, traceable editing via barcoded gRNAs
could provide valuable insights into the molecular mechanisms of
evolution. To overcome the constraints of limited DNA library size and
low DNA library-transformation efficiencies, some researchers have fused
the Cas9-variants with error-prone polymerases or deaminases such as AID
to create random mutations in the target
regions.[14-20] Mutations are commonly located in
an area adjacent to the target site spanning around 40 to 80 base pairs.
In recent years, there has been a rise in the use of targeted in vivo
mutagenesis tools such as cytidine/adenosine deaminase,
TRACE,[21] eMutaT7,[22] and
TRIDENT,[23] which are based on T7 RNA
polymerase-deaminase fusion proteins.[24-27]Deaminases greatly increase the mutation rate of the target region and
speed up evolution, while the use of T7 RNA polymerase (T7 RNAP) instead
of Cas9-variants broadens the editing window, allowing us to mutate
longer regions. Generation of genetic diversity is the foundation of
accelerating evolution, and developing mutagenesis tools with different
mutation types is of great importance in this process. However, there
are still some drawbacks in the above-mentioned techniques, such as low
mutation rate and mutation bias, which make them unable to fully meet
the needs of users for targeted mutagenesis.
In this work, we developed the targeted in vivo mutagenesis
system by fusing different DNA-modifying enzymes, cytidine deaminase and
T7 RNAP. We obtained three fusion proteins, MAG1/EXO1/REV3-PmCDA1-T7
RNAP, which could significantly increase the mutation rate and expand
the mutation spectrum. Our mutagenesis tools can complement the
above-mentioned platforms and accelerate the evolution of target genes.
Materials and Methods
Strain construction and cultivation
Escherichia coli -Trans1 T1 was used as the cloning and
amplification host. For plasmid construction, the heterologous gene
sequences were cloned from the previously published plasmids in Addgene.
The DNA-modifying enzymes were PCR amplified from the BY4741 genome. The
PCR products were connected to the pRS415 vector. Cloning was performed
by SE assembly and BM assembly followed by transformation into E.
coli- Trans1 T1. E. coli strains were cultivated at 37℃ in liquid
LB media (LB, 1% (w/v) tryptone, 0.5% (w/v) yeast extract, 1% (w/v)
NaCl) with appropriate antibiotics and selected on LB agar plates with
100μg/mL ampicillin.
BY4741 was used as the chassis strain in this work. The plasmids
carrying the mutagenesis cassettes were transformed into yeasts through
yeast transformation. The T7-CAN1 cassette was PCR amplified and
integrated into the genome using HIS3 as the selectable marker.Strains were grown at 30℃ in liquid YPD media (1% yeast extract, 2%
peptone, 2% glucose) and selected on SC agar plates lacking leucine,
leucine and uracil, or leucine and histidine.