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Fanconi anemia (Fanconi anemia, FA) is a serious human genetic disease that was first discovered and recorded in 1927 by the Swiss pediatrician Guido Fanconi
.
Its main manifestations are bone marrow failure, developmental malformations and cancer susceptibility
.
So far, it has been found that at least 22 Fanconi anemia genes (FANCA-W) mutations will cause the disease
.
The proteins expressed by these genes participate in a special DNA repair pathway-the FA pathway (FA pathway)
.
Because the cells of Fanconi anemia patients show super sensitivity to drugs that trigger interstrand crosslink (ICL)
.
Therefore, it has long been generally believed that the main function of the FA pathway is to repair ICL, and Fanconi anemia is caused by the repair defects of endogenous ICL
.
However, the endogenous inducers of ICL are still elusive
.
Recent genetic evidence in mice and humans indicates that endogenous aldehydes are the cause of FA disease
.
But aldehydes can not only cause ICLs, but also produce monoadducts and cause protein-DNA cross-linking, and can also generate replication pressure by affecting the metabolism of tetrahydrofolate
.
Therefore, it is still not certain which DNA damage repair defects ultimately lead to Fanconi anemia
.
On June 10, 2021, Xu Dongyi's group from the School of Life Sciences, Peking University and the State Key Laboratory of Protein and Plant Gene Research published in the journal Nature Structural & Molecular Biology the title: Fanconi anemia proteins participate in a break-induced-replication -like pathway to counter replication stress research paper
.
The study found that the FA pathway (FA pathway) is essentially a break-induced replication (BIR) pathway, used to repair stalled replication forks, and proposed that sustained replication pressure is a potential symptom of FA.
The point of view of endogenous etiology
.
Chromosomal DNA is at the core of the continuation of life, so the precise replication of DNA and the stable maintenance of the genome are of great significance
.
However, various disturbances from internal and external sources can interfere with the normal progress and completion of the replication process, creating replication stress
.
Replication pressure will slow down or even stop the advancement of replication forks, affecting DNA synthesis
.
Continued replication pressure will cause the replication fork to collapse, resulting in double-strand breaks.
This damage is extremely harmful to cells and living organisms and is difficult to repair
.
The stagnation of replication forks caused by replication pressure is also the main source of cancer cell genome rearrangement and mutations
.
Therefore, the repair and restart of damaged replication forks are of great significance to living organisms
.
Although FA protein has been shown to be involved in replication stress response, it is contrary to the fact that it has never been found that FA-deficient cells are sensitive to replication stress drugs for a long time.
.
The research team first verified this conclusion and found that FA gene-deficient cells are not sensitive to short-term treatment of replication stress drugs aphidicolin (APH) or hydroxyurea (HU)
.
Surprisingly, FA-deficient cell lines showed extremely high sensitivity to persistent replication stress drugs (APH or HU) treatment
.
This sensitivity comes from the gradual loss of chromosomes in FA-deficient cells under continuous replication pressure
.
Further immunofluorescence experiments found that the ultrafine DNA bridges (UFBs) and micronuclei produced by FA cells in the late division period increased significantly
.
In an early study, the research team found that stalled replication forks complete the restart process through two main pathways: the cutting-independent pathway that relies on 53BP1 in the early stage of replication stress, and the reliance on BRCA1 (also known as FANCS, this gene) in the late stage of replication stress.
Mutations also cause the break-induced replication (BIR) pathway of FA disease)
.
53BP1 and BRCA1 antagonistically regulate the choice of two stalled replication fork restart pathways under replication pressure
.
BIR is a unique homologous recombination (HR) mechanism used to repair single-ended DNA breaks
.
This pathway is also involved in the DNA synthesis process (Mitotic DNA Synthesis, MiDAS process) during the division period, and its deletion can lead to UFB and micronuclei
.
The authors of this study proved that FA protein plays an important role in the BRCA1-dependent BIR/MiDAS pathway.
FA protein acts on the downstream of BRCA1 to promote the cleavage of replication forks, thereby assisting the restarting of stalled replication forks
.
In further research, it was found that the BIR pathway and the FA pathway have a unified molecular mechanism: First, 53BP1-BRCA1 antagonistically regulates the initial step of the FA pathway—replication fork cleavage.
This antagonistic ability comes from their ability to restart the replication fork.
Secondly, the BIR pathway and the FA pathway both rely on the nuclease SLX4 and FAN1 to mediate the cleavage process of the replication fork; finally, they both rely on POLD3 to complete the DNA synthesis process
.
This shows that the FA pathway is essentially a BIR pathway
.
The model diagram of the involvement of FA protein in replication restart is based on the important role of FA protein in the BIR pathway under replication pressure.
The authors of this study speculate that replication pressure may be an endogenous factor that causes FA symptoms
.
In order to verify this conjecture, the research team constructed a FANCL-deficient mouse model.
After daily intraperitoneal injection of low-dose replication pressure drug HU, it was found that continuous replication pressure can trigger anemia symptoms in FANCL-deficient mice.
The mouse hematopoietic progenitor cells The abnormal function of proliferation and differentiation eventually triggers the bone marrow failure phenotype of FANCL-deficient mice
.
When looking for evidence of the physiological conditions associated with FA disease and replication stress, the research team found that replication stress can specifically induce the loss of chromosome 7 in human lymphatic TK6 cells with FANCC missing.
This phenomenon is similar to the frequent occurrence of FA patient cells.
The loss of chromosome 7 is consistent with the loss of chromosome, further indicating that continuous replication pressure is a potential endogenous cause of FA symptoms
.
HE stained sections of mouse femurs in the control and experimental groups (a) and cell mass statistics per unit area of bone marrow (b) This study reveals the essential function and molecular mechanism of the FA pathway, and explains the new mechanism of the pathogenesis of Fanconi's disease
.
This will not only help people prevent and treat symptoms such as bone marrow failure caused by FA gene mutations, but also help normal people prevent and treat premature blood system aging, and at the same time deepen everyone's understanding of the occurrence and development of cancer, which has important theoretical and clinical significance
.
Dr.
Xu Xinlin and Xu Yixi from the Xu Dongyi research group of Peking University School of Life Sciences are the co-first authors of the research paper
.
In addition, the research team Guo Ruiyuan, Xu Ran and Fu Congcong also contributed to the research
.
At the same time, the research was supported and helped by Li Qing's group at Peking University's School of Life Sciences, Minoru Takata's group at the Radiation Biology Research Center, Division of Life Sciences, Kyoto University, and Shunichi Takeda's group at the Department of Radiation Genetics, Kyoto University's School of Medicine
.
Paper link: https:// open for reprinting this article open for reprinting: just leave a message in this article and let us know
.
Its main manifestations are bone marrow failure, developmental malformations and cancer susceptibility
.
So far, it has been found that at least 22 Fanconi anemia genes (FANCA-W) mutations will cause the disease
.
The proteins expressed by these genes participate in a special DNA repair pathway-the FA pathway (FA pathway)
.
Because the cells of Fanconi anemia patients show super sensitivity to drugs that trigger interstrand crosslink (ICL)
.
Therefore, it has long been generally believed that the main function of the FA pathway is to repair ICL, and Fanconi anemia is caused by the repair defects of endogenous ICL
.
However, the endogenous inducers of ICL are still elusive
.
Recent genetic evidence in mice and humans indicates that endogenous aldehydes are the cause of FA disease
.
But aldehydes can not only cause ICLs, but also produce monoadducts and cause protein-DNA cross-linking, and can also generate replication pressure by affecting the metabolism of tetrahydrofolate
.
Therefore, it is still not certain which DNA damage repair defects ultimately lead to Fanconi anemia
.
On June 10, 2021, Xu Dongyi's group from the School of Life Sciences, Peking University and the State Key Laboratory of Protein and Plant Gene Research published in the journal Nature Structural & Molecular Biology the title: Fanconi anemia proteins participate in a break-induced-replication -like pathway to counter replication stress research paper
.
The study found that the FA pathway (FA pathway) is essentially a break-induced replication (BIR) pathway, used to repair stalled replication forks, and proposed that sustained replication pressure is a potential symptom of FA.
The point of view of endogenous etiology
.
Chromosomal DNA is at the core of the continuation of life, so the precise replication of DNA and the stable maintenance of the genome are of great significance
.
However, various disturbances from internal and external sources can interfere with the normal progress and completion of the replication process, creating replication stress
.
Replication pressure will slow down or even stop the advancement of replication forks, affecting DNA synthesis
.
Continued replication pressure will cause the replication fork to collapse, resulting in double-strand breaks.
This damage is extremely harmful to cells and living organisms and is difficult to repair
.
The stagnation of replication forks caused by replication pressure is also the main source of cancer cell genome rearrangement and mutations
.
Therefore, the repair and restart of damaged replication forks are of great significance to living organisms
.
Although FA protein has been shown to be involved in replication stress response, it is contrary to the fact that it has never been found that FA-deficient cells are sensitive to replication stress drugs for a long time.
.
The research team first verified this conclusion and found that FA gene-deficient cells are not sensitive to short-term treatment of replication stress drugs aphidicolin (APH) or hydroxyurea (HU)
.
Surprisingly, FA-deficient cell lines showed extremely high sensitivity to persistent replication stress drugs (APH or HU) treatment
.
This sensitivity comes from the gradual loss of chromosomes in FA-deficient cells under continuous replication pressure
.
Further immunofluorescence experiments found that the ultrafine DNA bridges (UFBs) and micronuclei produced by FA cells in the late division period increased significantly
.
In an early study, the research team found that stalled replication forks complete the restart process through two main pathways: the cutting-independent pathway that relies on 53BP1 in the early stage of replication stress, and the reliance on BRCA1 (also known as FANCS, this gene) in the late stage of replication stress.
Mutations also cause the break-induced replication (BIR) pathway of FA disease)
.
53BP1 and BRCA1 antagonistically regulate the choice of two stalled replication fork restart pathways under replication pressure
.
BIR is a unique homologous recombination (HR) mechanism used to repair single-ended DNA breaks
.
This pathway is also involved in the DNA synthesis process (Mitotic DNA Synthesis, MiDAS process) during the division period, and its deletion can lead to UFB and micronuclei
.
The authors of this study proved that FA protein plays an important role in the BRCA1-dependent BIR/MiDAS pathway.
FA protein acts on the downstream of BRCA1 to promote the cleavage of replication forks, thereby assisting the restarting of stalled replication forks
.
In further research, it was found that the BIR pathway and the FA pathway have a unified molecular mechanism: First, 53BP1-BRCA1 antagonistically regulates the initial step of the FA pathway—replication fork cleavage.
This antagonistic ability comes from their ability to restart the replication fork.
Secondly, the BIR pathway and the FA pathway both rely on the nuclease SLX4 and FAN1 to mediate the cleavage process of the replication fork; finally, they both rely on POLD3 to complete the DNA synthesis process
.
This shows that the FA pathway is essentially a BIR pathway
.
The model diagram of the involvement of FA protein in replication restart is based on the important role of FA protein in the BIR pathway under replication pressure.
The authors of this study speculate that replication pressure may be an endogenous factor that causes FA symptoms
.
In order to verify this conjecture, the research team constructed a FANCL-deficient mouse model.
After daily intraperitoneal injection of low-dose replication pressure drug HU, it was found that continuous replication pressure can trigger anemia symptoms in FANCL-deficient mice.
The mouse hematopoietic progenitor cells The abnormal function of proliferation and differentiation eventually triggers the bone marrow failure phenotype of FANCL-deficient mice
.
When looking for evidence of the physiological conditions associated with FA disease and replication stress, the research team found that replication stress can specifically induce the loss of chromosome 7 in human lymphatic TK6 cells with FANCC missing.
This phenomenon is similar to the frequent occurrence of FA patient cells.
The loss of chromosome 7 is consistent with the loss of chromosome, further indicating that continuous replication pressure is a potential endogenous cause of FA symptoms
.
HE stained sections of mouse femurs in the control and experimental groups (a) and cell mass statistics per unit area of bone marrow (b) This study reveals the essential function and molecular mechanism of the FA pathway, and explains the new mechanism of the pathogenesis of Fanconi's disease
.
This will not only help people prevent and treat symptoms such as bone marrow failure caused by FA gene mutations, but also help normal people prevent and treat premature blood system aging, and at the same time deepen everyone's understanding of the occurrence and development of cancer, which has important theoretical and clinical significance
.
Dr.
Xu Xinlin and Xu Yixi from the Xu Dongyi research group of Peking University School of Life Sciences are the co-first authors of the research paper
.
In addition, the research team Guo Ruiyuan, Xu Ran and Fu Congcong also contributed to the research
.
At the same time, the research was supported and helped by Li Qing's group at Peking University's School of Life Sciences, Minoru Takata's group at the Radiation Biology Research Center, Division of Life Sciences, Kyoto University, and Shunichi Takeda's group at the Department of Radiation Genetics, Kyoto University's School of Medicine
.
Paper link: https:// open for reprinting this article open for reprinting: just leave a message in this article and let us know
