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Mutations

Mutations

Mutations are changes in the sequence of DNA. These changes can occur spontaneously or they can be induced by exposure to environmental factors. Mutations can be characterized in a number of different ways: whether and how they alter the amino acid sequence of the protein, whether they occur over a small or large area of DNA, and whether they occur in somatic cells or germline cells.
Chromosomal Alterations Are Large-Scale Mutations
While point mutations are changes in a single nucleotide in...

Mutations

Mutations

Mismatch Repair

Mismatch Repair

Organisms are capable of detecting and fixing nucleotide mismatches that occur during DNA replication. This sophisticated process requires identifying the new strand and replacing the erroneous bases with correct nucleotides. Mismatch repair is coordinated by many proteins in both prokaryotes and eukaryotes.
The Mutator Protein Family Plays a Key Role in DNA Mismatch Repair
The human genome has more than 3 billion base pairs of DNA per cell. Prior to cell division, that vast amount of genetic...

Point and Frameshift Mutations

Point and Frameshift Mutations

Point mutations are genetic alterations involving the change of a single nucleotide base pair in DNA. Depending on how the alteration affects protein synthesis, they can lead to various consequences.Point mutations fall into the following types:Silent mutations occur when a nucleotide change does not alter the amino acid sequence due to the redundancy of the genetic code. For instance, changing ACC to ACA still encodes threonine, leaving the protein function unaffected. This occurs because...

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Related Experiment Video

Updated: Jan 7, 2026

Production of Human CRISPR-Engineered CAR-T Cells

Production of Human CRISPR-Engineered CAR-T Cells

Published on: March 15, 2021

Base-editing a single missense mutation in A20 enhances CAR-T cell efficacy.

Adam Blaisdell¹, Stefanie Bachl^1,2, Luis R Sandoval^2,3

¹Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.

Biorxiv : the Preprint Server for Biology

|December 25, 2025

Summary

Scientists identified A20/TNFAIP3 as a key regulator of T cell exhaustion in cancer immunotherapy. Targeting its A20^ZF7 motif with base-editing enhances anti-tumor T cell function and cancer suppression.

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Last Updated: Jan 7, 2026

Production of Human CRISPR-Engineered CAR-T Cells

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Published on: March 15, 2021

Engineering Oncogenic Heterozygous Gain-of-Function Mutations in Human Hematopoietic Stem and Progenitor Cells

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Published on: March 10, 2023

Using CRISPR/Cas9 to Knock Out GM-CSF in CAR-T Cells

Using CRISPR/Cas9 to Knock Out GM-CSF in CAR-T Cells

Published on: July 22, 2019

Area of Science:

Immunology
Molecular Biology
Cancer Research

Background:

T cell exhaustion hinders cancer immunotherapy effectiveness.
Identifying regulators of T cell exhaustion is crucial for improving treatments.

Purpose of the Study:

To identify novel regulators of T cell exhaustion.
To investigate the role of A20/TNFAIP3 in T cell persistence and anti-tumor immunity.
To explore base-editing strategies for enhancing CAR-T cell therapy.

Main Methods:

Genome-wide loss-of-function screening in human T cells.
Protein large language modeling and deep base-editing mutagenesis.
In vivo studies using immunocompetent mice and engineered CAR-T cells.

Main Results:

A20/TNFAIP3 identified as a major negative regulator of exhausted T cell persistence.
A20's M1 ubiquitin-binding zinc finger 7 (A20^ZF7) motif is critical for suppressing anti-tumor immunity.
A20^ZF7-deficient T cells resisted exhaustion, enhanced perforin degranulation, and improved tumor suppression.
Base-edited human CAR-T cells targeting A20^ZF7 resisted exhaustion and demonstrated potent anti-cancer activity in vivo.

Conclusions:

A20^ZF7 is a novel T cell checkpoint that suppresses anti-tumor immunity.
Precision base-editing of missense mutations offers a promising strategy to enhance CAR-T cell therapy efficacy.