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Responsible editor | Xi antibody plays a key role in the body's anti-infection immunity (such as anti-coronavirus infection) and the effect of vaccines
.
After being activated by the antigen, the variable region of the immunoglobulin gene in the B cell undergoes somatic hypermutation (SHM) to produce high-affinity antibodies; its constant region is transformed by class switch recombination.
, CSR), to produce antibodies of different subtypes (such as switching from IgM to IgG or IgA), thereby mediating the diversification of antibody functions
.
Both processes are mediated by "activation-induced cytidine deaminase" (AID)
.
AID can deaminate cytosine into uracil, causing mismatches of uracil/guanine in the immunoglobulin gene region
.
This mismatch is recognized and processed by DNA repair pathways (such as base excision repair (BER) and mismatch repair (MMR)), which will induce DNA mutations in the immunoglobulin gene region
.
These B cells with DNA mutations are selected in the germinal center based on their ability to bind to the antigen, which ultimately leads to the production of high-affinity antibodies
.
Although AID has been discovered as early as 20 years ago, the complete mechanism of its action and the molecular pathway of uracil mutation treatment are still unknown
.
Uracil, as a "heterogeneous" base appearing in DNA, is usually quickly affected by the "Uracil DNA glycosylase" (UNG) in the base excision repair pathway.
Recognition and excision to generate abasic sites, which trigger high-fidelity repairs on other members of the pathway to maintain the stability and integrity of the genome
.
However, in the process of B cell antibody diversification, what mechanism causes AID-mediated uracil to be mutated instead of being repaired quickly and with high fidelity.
This is a major problem that has plagued immunologists for decades
.
On November 24, 2021, Alberto Martin's team from the Department of Immunology of the University of Toronto in Canada published an article FAM72A antagonizes UNG2 to promote mutagenic repair during antibody maturation in Nature, reporting a major discovery of the mechanism of B cell antibody diversification
.
The research team conducted genome-wide CRISPR screening on the CH12F3-2 B cell line and identified FAM72A as a key role in the CSR process of B cells
.
Subsequently, by constructing Fam72a knockout mice, the team found that compared with wild-type B cells, primary B cells derived from Fam72a knockout mice had an antibody type switch (CSR; occurred in the antibody constant change region) The frequency of somatic hypermutation (SHM; occurs in the variable region of an antibody and can lead to an increase in antibody affinity) is significantly reduced
.
In terms of the mechanism of action, the authors found that FAM72A can inhibit the protein expression level of UNG
.
When cells lack FAM72A, the protein level and activity of UNG are significantly increased, leading to the high efficiency of AID-induced uracil recognition and repair, which in turn reduces the frequency of B cell mutations
.
The activity of AID is closely related to cell cycle regulation
.
In the G1 phase, AID acts on the single-stranded DNA produced by gene transcription to deaminate cytosine into uracil
.
Using cyclin inhibitors to lock cells in a specific proliferation cycle, the authors found that FAM72A is also highly expressed during G1, which in turn significantly reduces the expression of UNG during G1
.
The low expression of UNG causes the uracil to be unable to be repaired in time in the G1 phase, so that the uracil in the DNA sequence continues to the S phase
.
In the S phase, DNA replication from abasic sites mediated by uracil or UNG will cause mutations
.
In short, by regulating the protein level of UNG, the presence of FAM72A allows AID to fully play its role as a "mutagenic", triggering mutations in the coding region of B cell immunoglobulins, thereby mediating the production of high-affinity antibodies and antibodies of different subtypes
.
Professor Alberto Martin is the corresponding author of the article, and Dr.
Feng Yuqing and Dr.
Conglei Li are the co-first authors of the Nature article
.
Dr.
Li Conglei has established an independent research group (https://med.
cuhk.
edu.
cn/teacher/159) at the Chinese University of Hong Kong (Shenzhen) School of Medicine.
The main research directions are B cell antibody production mechanism, intestinal mucosal immunity, And the regulation mechanism of stromal cell microenvironment on immune cell function
.
The laboratory currently recruits post-doctoral and doctoral students, and young talents who are interested in the above research directions are welcome to join (see: https:// for details)
.
It is worth mentioning that during the same period, the Bernardo Reina-San-Martin laboratory of the French Institute of Genetics and Molecular and Cell Biology (IGBMC) published a back-to-back article in Nature: Fam72a enforces error-prone DNA repair during antibody diversification
.
In this study, the Reina-San-Martin research team used experimental methods similar to those of Alberto Martin's team, namely the B cell line genome-wide CRISPR screening and the construction of Fam72a knockout mice
.
Two independent research teams have made similar major discoveries about the mechanism of B cell antibody production
.
Original link: https:// Plate maker: Notes for reprinting on the 11th [Non-original article] The copyright of this article belongs to the author of the article, personal forwarding and sharing are welcome, and it is prohibited without permission Reprinted, the author has all legal rights, offenders must be investigated
.
.
After being activated by the antigen, the variable region of the immunoglobulin gene in the B cell undergoes somatic hypermutation (SHM) to produce high-affinity antibodies; its constant region is transformed by class switch recombination.
, CSR), to produce antibodies of different subtypes (such as switching from IgM to IgG or IgA), thereby mediating the diversification of antibody functions
.
Both processes are mediated by "activation-induced cytidine deaminase" (AID)
.
AID can deaminate cytosine into uracil, causing mismatches of uracil/guanine in the immunoglobulin gene region
.
This mismatch is recognized and processed by DNA repair pathways (such as base excision repair (BER) and mismatch repair (MMR)), which will induce DNA mutations in the immunoglobulin gene region
.
These B cells with DNA mutations are selected in the germinal center based on their ability to bind to the antigen, which ultimately leads to the production of high-affinity antibodies
.
Although AID has been discovered as early as 20 years ago, the complete mechanism of its action and the molecular pathway of uracil mutation treatment are still unknown
.
Uracil, as a "heterogeneous" base appearing in DNA, is usually quickly affected by the "Uracil DNA glycosylase" (UNG) in the base excision repair pathway.
Recognition and excision to generate abasic sites, which trigger high-fidelity repairs on other members of the pathway to maintain the stability and integrity of the genome
.
However, in the process of B cell antibody diversification, what mechanism causes AID-mediated uracil to be mutated instead of being repaired quickly and with high fidelity.
This is a major problem that has plagued immunologists for decades
.
On November 24, 2021, Alberto Martin's team from the Department of Immunology of the University of Toronto in Canada published an article FAM72A antagonizes UNG2 to promote mutagenic repair during antibody maturation in Nature, reporting a major discovery of the mechanism of B cell antibody diversification
.
The research team conducted genome-wide CRISPR screening on the CH12F3-2 B cell line and identified FAM72A as a key role in the CSR process of B cells
.
Subsequently, by constructing Fam72a knockout mice, the team found that compared with wild-type B cells, primary B cells derived from Fam72a knockout mice had an antibody type switch (CSR; occurred in the antibody constant change region) The frequency of somatic hypermutation (SHM; occurs in the variable region of an antibody and can lead to an increase in antibody affinity) is significantly reduced
.
In terms of the mechanism of action, the authors found that FAM72A can inhibit the protein expression level of UNG
.
When cells lack FAM72A, the protein level and activity of UNG are significantly increased, leading to the high efficiency of AID-induced uracil recognition and repair, which in turn reduces the frequency of B cell mutations
.
The activity of AID is closely related to cell cycle regulation
.
In the G1 phase, AID acts on the single-stranded DNA produced by gene transcription to deaminate cytosine into uracil
.
Using cyclin inhibitors to lock cells in a specific proliferation cycle, the authors found that FAM72A is also highly expressed during G1, which in turn significantly reduces the expression of UNG during G1
.
The low expression of UNG causes the uracil to be unable to be repaired in time in the G1 phase, so that the uracil in the DNA sequence continues to the S phase
.
In the S phase, DNA replication from abasic sites mediated by uracil or UNG will cause mutations
.
In short, by regulating the protein level of UNG, the presence of FAM72A allows AID to fully play its role as a "mutagenic", triggering mutations in the coding region of B cell immunoglobulins, thereby mediating the production of high-affinity antibodies and antibodies of different subtypes
.
Professor Alberto Martin is the corresponding author of the article, and Dr.
Feng Yuqing and Dr.
Conglei Li are the co-first authors of the Nature article
.
Dr.
Li Conglei has established an independent research group (https://med.
cuhk.
edu.
cn/teacher/159) at the Chinese University of Hong Kong (Shenzhen) School of Medicine.
The main research directions are B cell antibody production mechanism, intestinal mucosal immunity, And the regulation mechanism of stromal cell microenvironment on immune cell function
.
The laboratory currently recruits post-doctoral and doctoral students, and young talents who are interested in the above research directions are welcome to join (see: https:// for details)
.
It is worth mentioning that during the same period, the Bernardo Reina-San-Martin laboratory of the French Institute of Genetics and Molecular and Cell Biology (IGBMC) published a back-to-back article in Nature: Fam72a enforces error-prone DNA repair during antibody diversification
.
In this study, the Reina-San-Martin research team used experimental methods similar to those of Alberto Martin's team, namely the B cell line genome-wide CRISPR screening and the construction of Fam72a knockout mice
.
Two independent research teams have made similar major discoveries about the mechanism of B cell antibody production
.
Original link: https:// Plate maker: Notes for reprinting on the 11th [Non-original article] The copyright of this article belongs to the author of the article, personal forwarding and sharing are welcome, and it is prohibited without permission Reprinted, the author has all legal rights, offenders must be investigated
.
