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Editor-in-Chief | Fanconi anemia (Fanconi anemia, FA) is a serious human genetic disease.
It was originally discovered and recorded by Swiss pediatrician Guido Fanconi in 1927 [1]
.
Its main manifestations are bone marrow failure (BMF), developmental abnormalities and cancer susceptibility
.
So far, it has been found that at least 22 FA gene (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 patients with FA show ultra-high 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 FA diseases are 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 [2,3]
.
But aldehydes can not only cause ICLs, but also produce monoadducts [4], cause protein-DNA cross-linking [5], and can also generate replication pressure by affecting the metabolism of tetrahydrofolate [6]
.
Therefore, it is still uncertain which DNA damage repair defects ultimately lead to FA disease
.
On June 10, 2021, the research group of Dongyi Xu from the School of Life Sciences, Peking University published an article Fanconi anemia proteins participate in a break-induced-replication-like pathway to counter replication stress on Nature Structural & Molecular Biology, and found that the FA pathway is essentially A break-induced replication (BIR) pathway is used to repair stagnant replication forks, and the view that sustained replication pressure is a potential endogenous cause of FA symptoms
.
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 the FA protein has been shown to be involved in the replication stress response, contrary to it, the sensitivity of FA-deficient cells to replication stress drugs has never been found for a long time [7-9]
.
The authors of the study 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
.
The research experimental group found in an earlier study [10] 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 pressure, and the dependence on BRCA1 (also known as BRCA1) in the late stage of replication pressure.
For FANCS, mutations in this gene 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
.
Figure 1.
The model diagram of FA protein involved in replication restart.
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 authors of this study constructed a FANCL-deficient mouse model.
After daily intraperitoneal injection of low-dose replication pressure drug HU, they found that continuous replication pressure can trigger anemia symptoms in FANCL-deficient mice.
The mouse hematopoietic progenitor The abnormal function of cell proliferation and differentiation eventually triggers the bone marrow failure phenotype of FANCL-deficient mice
.
When looking for evidence of the physiological conditions related to FA disease and replication stress, the authors of this study found that replication stress can specifically induce the loss of chromosome 7 in human lymphatic TK6 cells lacking FANCC.
This phenomenon is consistent with the frequency of cells in FA patients.
The loss of chromosome 7 in the hair is consistent, which further indicates that continuous replication pressure is a potential endogenous cause of FA symptoms
.
This study revealed the essential function and molecular mechanism of the FA pathway, and explained a new mechanism for 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, a postdoctoral fellow of Xu Dong from the School of Life Sciences, Peking University, are the co-first authors of the research paper
.
In addition, Guo Ruiyuan, Xu Ran and Fu Congcong from this group 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 Graduate School of Medicine
.
Original link: https:// Platemaker: 11 References 1.
Bogliolo M, Surrallés J.
Fanconi anemia: a model disease for studies on human genetics and advanced therapeutics.
Current opinion in genetics & development.
2015 2015/08/01/;33:32-40.
doi:https://doi.
org/10.
1016/j.
gde.
2015.
07.
002.
2.
Langevin F, Crossan GP, Rosado IV, Arends MJ, Patel KJ.
Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice.
Nature.
2011 Jul 6;475(7354):53-8.
eng.
Epub 2011/07/08.
doi:10.
1038/nature10192.
Cited in: Pubmed; PMID 21734703.
3.
Hira A, Yabe H, Yoshida K, Okuno Y, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Nakamura J, Kojima S, Ogawa S, Matsuo K, Takata M, Yabe M.
Variant ALDH2 is associated with accelerated progression of bone marrow failure in Japanese Fanconi anemia patients.
Blood.
2013 2013/10/31/;122(18):3206-3209.
doi:https://doi.
org/10.
1182/blood-2013-06-507962.
4.
Duxin JP, Walter JC.
What is the DNA repair defect underlying Fanconi anemia? Current Opinion in Cell Biology.
2015 2015/12/01/;37: 49-60.
doi:https://doi.
org/10.
1016/j.
ceb.
2015.
09.
002.
5.
Cohen Hubal EA, Schlosser PM, Conolly RB, Kimbell JS.
Comparison of Inhaled Formaldehyde Dosimetry Predictions with DNA--Protein Cross-Link Measurements in the Rat Nasal Passages.
Toxicology and Applied Pharmacology.
1997 1997/03/01/;143(1):47-55.
doi:https://doi.
org/10.
1006/taap.
1996.
8076.
6.
Garcia-Calderon CB, Bejarano-Garcia JA, Tinoco-Gago I, Castro MJ, Moreno-Gordillo P, Piruat JI, Caballero-Velazquez T, Perez-Simon JA, Rosado IV.
Genotoxicity of tetrahydrofolic acid to hematopoietic stem and progenitor cells.
Cell Death Differ .
2018 Nov;25(11):1967-1979.
Epub 2018/03/08.
doi:10.
1038/s41418-018-0089-4.
Cited in:Pubmed; PMID 29511342.
7.
Schlacher K, Wu H, Jasin M.
A distinct replication fork protection pathway connects Fanconi anemia tumor suppressors to RAD51-BRCA1/2.
Cancer cell.
2012 Jul 10;22(1):106-16.
eng.
Epub 2012/07/14.
doi:10.
1016/j.
ccr.
2012.
05.
015.
Cited in: Pubmed; PMID 22789542.
8.
Tian Y, Shen X, Wang R, Klages-Mundt NL, Lynn EJ, Martin SK, Ye Y, Gao M, Chen J, Schlacher K, Li L.
Constitutive role of the Fanconi anemia D2 gene in the replication stress response.
The Journal of biological chemistry.
2017 Dec 8;292(49):20184-20195.
eng.
Epub 2017/ 10/13.
doi:10.
1074/jbc.
M117.
814780.
Cited in: Pubmed; PMID 29021208.
9.
Chen X, Bosques L, Sung P, Kupfer GM.
A novel role for non-ubiquitinated FANCD2 in response to hydroxyurea-induced DNA damage .
Oncogene.
2016 Jan 7;35(1):22-34.
eng.
Epub 2015/04/22.
doi:10.
1038/onc.
2015.
68.
Cited in: Pubmed;PMID 25893307.
10.
Xu Y, Ning S, Wei Z, Xu R, Xu X, Xing M, Guo R, Xu D.
53BP1 and BRCA1 control pathway choice for stalled replication restart.
eLife.
2017;6.
doi:10.
7554/eLife.
30523.
(Swipe up and down to read) Reprint instructions [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights, and offenders must be investigated. .
It was originally discovered and recorded by Swiss pediatrician Guido Fanconi in 1927 [1]
.
Its main manifestations are bone marrow failure (BMF), developmental abnormalities and cancer susceptibility
.
So far, it has been found that at least 22 FA gene (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 patients with FA show ultra-high 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 FA diseases are 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 [2,3]
.
But aldehydes can not only cause ICLs, but also produce monoadducts [4], cause protein-DNA cross-linking [5], and can also generate replication pressure by affecting the metabolism of tetrahydrofolate [6]
.
Therefore, it is still uncertain which DNA damage repair defects ultimately lead to FA disease
.
On June 10, 2021, the research group of Dongyi Xu from the School of Life Sciences, Peking University published an article Fanconi anemia proteins participate in a break-induced-replication-like pathway to counter replication stress on Nature Structural & Molecular Biology, and found that the FA pathway is essentially A break-induced replication (BIR) pathway is used to repair stagnant replication forks, and the view that sustained replication pressure is a potential endogenous cause of FA symptoms
.
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 the FA protein has been shown to be involved in the replication stress response, contrary to it, the sensitivity of FA-deficient cells to replication stress drugs has never been found for a long time [7-9]
.
The authors of the study 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
.
The research experimental group found in an earlier study [10] 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 pressure, and the dependence on BRCA1 (also known as BRCA1) in the late stage of replication pressure.
For FANCS, mutations in this gene 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
.
Figure 1.
The model diagram of FA protein involved in replication restart.
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 authors of this study constructed a FANCL-deficient mouse model.
After daily intraperitoneal injection of low-dose replication pressure drug HU, they found that continuous replication pressure can trigger anemia symptoms in FANCL-deficient mice.
The mouse hematopoietic progenitor The abnormal function of cell proliferation and differentiation eventually triggers the bone marrow failure phenotype of FANCL-deficient mice
.
When looking for evidence of the physiological conditions related to FA disease and replication stress, the authors of this study found that replication stress can specifically induce the loss of chromosome 7 in human lymphatic TK6 cells lacking FANCC.
This phenomenon is consistent with the frequency of cells in FA patients.
The loss of chromosome 7 in the hair is consistent, which further indicates that continuous replication pressure is a potential endogenous cause of FA symptoms
.
This study revealed the essential function and molecular mechanism of the FA pathway, and explained a new mechanism for 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, a postdoctoral fellow of Xu Dong from the School of Life Sciences, Peking University, are the co-first authors of the research paper
.
In addition, Guo Ruiyuan, Xu Ran and Fu Congcong from this group 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 Graduate School of Medicine
.
Original link: https:// Platemaker: 11 References 1.
Bogliolo M, Surrallés J.
Fanconi anemia: a model disease for studies on human genetics and advanced therapeutics.
Current opinion in genetics & development.
2015 2015/08/01/;33:32-40.
doi:https://doi.
org/10.
1016/j.
gde.
2015.
07.
002.
2.
Langevin F, Crossan GP, Rosado IV, Arends MJ, Patel KJ.
Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice.
Nature.
2011 Jul 6;475(7354):53-8.
eng.
Epub 2011/07/08.
doi:10.
1038/nature10192.
Cited in: Pubmed; PMID 21734703.
3.
Hira A, Yabe H, Yoshida K, Okuno Y, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Nakamura J, Kojima S, Ogawa S, Matsuo K, Takata M, Yabe M.
Variant ALDH2 is associated with accelerated progression of bone marrow failure in Japanese Fanconi anemia patients.
Blood.
2013 2013/10/31/;122(18):3206-3209.
doi:https://doi.
org/10.
1182/blood-2013-06-507962.
4.
Duxin JP, Walter JC.
What is the DNA repair defect underlying Fanconi anemia? Current Opinion in Cell Biology.
2015 2015/12/01/;37: 49-60.
doi:https://doi.
org/10.
1016/j.
ceb.
2015.
09.
002.
5.
Cohen Hubal EA, Schlosser PM, Conolly RB, Kimbell JS.
Comparison of Inhaled Formaldehyde Dosimetry Predictions with DNA--Protein Cross-Link Measurements in the Rat Nasal Passages.
Toxicology and Applied Pharmacology.
1997 1997/03/01/;143(1):47-55.
doi:https://doi.
org/10.
1006/taap.
1996.
8076.
6.
Garcia-Calderon CB, Bejarano-Garcia JA, Tinoco-Gago I, Castro MJ, Moreno-Gordillo P, Piruat JI, Caballero-Velazquez T, Perez-Simon JA, Rosado IV.
Genotoxicity of tetrahydrofolic acid to hematopoietic stem and progenitor cells.
Cell Death Differ .
2018 Nov;25(11):1967-1979.
Epub 2018/03/08.
doi:10.
1038/s41418-018-0089-4.
Cited in:Pubmed; PMID 29511342.
7.
Schlacher K, Wu H, Jasin M.
A distinct replication fork protection pathway connects Fanconi anemia tumor suppressors to RAD51-BRCA1/2.
Cancer cell.
2012 Jul 10;22(1):106-16.
eng.
Epub 2012/07/14.
doi:10.
1016/j.
ccr.
2012.
05.
015.
Cited in: Pubmed; PMID 22789542.
8.
Tian Y, Shen X, Wang R, Klages-Mundt NL, Lynn EJ, Martin SK, Ye Y, Gao M, Chen J, Schlacher K, Li L.
Constitutive role of the Fanconi anemia D2 gene in the replication stress response.
The Journal of biological chemistry.
2017 Dec 8;292(49):20184-20195.
eng.
Epub 2017/ 10/13.
doi:10.
1074/jbc.
M117.
814780.
Cited in: Pubmed; PMID 29021208.
9.
Chen X, Bosques L, Sung P, Kupfer GM.
A novel role for non-ubiquitinated FANCD2 in response to hydroxyurea-induced DNA damage .
Oncogene.
2016 Jan 7;35(1):22-34.
eng.
Epub 2015/04/22.
doi:10.
1038/onc.
2015.
68.
Cited in: Pubmed;PMID 25893307.
10.
Xu Y, Ning S, Wei Z, Xu R, Xu X, Xing M, Guo R, Xu D.
53BP1 and BRCA1 control pathway choice for stalled replication restart.
eLife.
2017;6.
doi:10.
7554/eLife.
30523.
(Swipe up and down to read) Reprint instructions [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights, and offenders must be investigated. .
