Back

TREX1 restricts CRISPR-Cas9 genome editing in human cells

Karasu, M. E.; Toufektchan, E.; Maciejowski, J.; Corn, J. E.

2022-12-13 molecular biology
10.1101/2022.12.12.520063 bioRxiv
Show abstract

CRISPR-Cas mediated homology-directed repair (HDR) can flexibly introduce desired mutations at targeted sites in a genome. But achieving high HDR efficiencies is a major hurdle in many cellular contexts. Moreover, cells from patients with mutations in DNA repair factors can exhibit low CRISPR-Cas-mediated HDR, complicating genome editing as a potential treatment. We used genome-wide screening in Fanconi anemia (FA) patient lymphoblastic cell lines to uncover suppressors of CRISPR-Cas mediated HDR. Surprisingly, we found that a single exonuclease called TREX1 is an important determinant of HDR efficiency when single-stranded templates are used as a repair template. TREX1 expression acts as a biomarker for CRISPR-Cas mediated HDR, such that cell lines expressing high levels of TREX1 have poor HDR that can be rescued by TREX1 removal. CRISPR-Cas mediated HDR can also be rescued by using single-stranded DNA templates that are chemically protected in a manner consistent with TREX1s exonucleolytic activity. Overall, our data provide a mechanistic explanation for why some cells are easier to edit than others and suggest a route to increase CRISPR-Cas mediated HDR in TREX-expressing context.

Matching journals

The top 5 journals account for 50% of the predicted probability mass.

1
Nature Communications
○ 5641 papers in training set
Top 4%
28.2%
Similar papers in this journal
2
Nucleic Acids Research
◐ 1281 papers in training set
Top 3%
7.2%
Similar papers in this journal
3
The CRISPR Journal
○ 39 papers in training set
Top 0.1%
6.2%
Similar papers in this journal
4
eLife
● 5828 papers in training set
Top 22%
5.5%
Similar papers in this journal
5
Proceedings of the National Academy of Sciences
● 2444 papers in training set
Top 8%
5.4%
Similar papers in this journal
50% of probability mass above
6
Molecular Therapy
○ 81 papers in training set
Top 0.3%
4.8%
7
Communications Biology
○ 993 papers in training set
Top 6%
3.2%
8
Science Advances
● 1243 papers in training set
Top 12%
3.1%
9
Scientific Reports
○ 3612 papers in training set
Top 37%
2.7%
10
Molecular Therapy - Nucleic Acids
○ 25 papers in training set
Top 0.2%
2.1%
11
Cell Reports
○ 1498 papers in training set
Top 17%
2.1%
12
Molecular Cell
○ 350 papers in training set
Top 3%
1.9%
13
The EMBO Journal
○ 309 papers in training set
Top 3%
1.9%
14
Molecular Therapy - Methods & Clinical Development
○ 38 papers in training set
Top 0.4%
1.4%
15
ACS Synthetic Biology
● 287 papers in training set
Top 2%
1.3%
16
ACS Chemical Biology
● 167 papers in training set
Top 2%
1.1%
17
Life Science Alliance
● 285 papers in training set
Top 5%
1.1%
18
Nature Biotechnology
○ 172 papers in training set
Top 4%
1.0%
19
npj Genomic Medicine
○ 36 papers in training set
Top 0.9%
0.8%
20
Nature Genetics
○ 286 papers in training set
Top 5%
0.8%
21
iScience
○ 1154 papers in training set
Top 36%
0.8%
22
Genome Biology
○ 637 papers in training set
Top 9%
0.8%
23
EMBO Reports
○ 263 papers in training set
Top 7%
0.8%
24
Nature Structural & Molecular Biology
236 papers in training set
Top 4%
0.6%
25
Journal of Biological Chemistry
○ 690 papers in training set
Top 11%
0.6%
26
Genes & Development
● 90 papers in training set
Top 2%
0.6%

"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.