Fan1 deficiency results in DNA interstrand cross-link repair defects, enhanced tissue karyomegaly, and organ dysfunction
| العنوان: | Fan1 deficiency results in DNA interstrand cross-link repair defects, enhanced tissue karyomegaly, and organ dysfunction |
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| المؤلفون: | Marina A. Bellani, Yanglu Chen, Supawat Thongthip, Siobhan Q. Gregg, Agata Smogorzewska, Sunandini Sridhar, Michael M. Seidman, Brooke A. Conti |
| المصدر: | Genes & Development. 30:645-659 |
| بيانات النشر: | Cold Spring Harbor Laboratory, 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | 0301 basic medicine, DNA Interstrand Cross-Link Repair, DNA Repair, DNA damage, DNA repair, Biology, Kidney, Mice, 03 medical and health sciences, Bone Marrow, Fanconi anemia, hemic and lymphatic diseases, FANCD2, Genetics, medicine, Animals, Endodeoxyribonucleases, Liver Diseases, FAN1, Epistasis, Genetic, Endonucleases, medicine.disease, Multifunctional Enzymes, Protein Structure, Tertiary, DNA-Binding Proteins, Karyomegaly, Disease Models, Animal, Protein Transport, Cross-Linking Reagents, Exodeoxyribonucleases, 030104 developmental biology, Liver, Cancer research, Interstrand cross-link repair, Research Paper, DNA Damage, Developmental Biology |
| الوصف: | Deficiency of FANCD2/FANCI-associated nuclease 1 (FAN1) in humans leads to karyomegalic interstitial nephritis (KIN), a rare hereditary kidney disease characterized by chronic renal fibrosis, tubular degeneration, and characteristic polyploid nuclei in multiple tissues. The mechanism of how FAN1 protects cells is largely unknown but is thought to involve FAN1's function in DNA interstrand cross-link (ICL) repair. Here, we describe a Fan1-deficient mouse and show that FAN1 is required for cellular and organismal resistance to ICLs. We show that the ubiquitin-binding zinc finger (UBZ) domain of FAN1, which is needed for interaction with FANCD2, is not required for the initial rapid recruitment of FAN1 to ICLs or for its role in DNA ICL resistance. Epistasis analyses reveal that FAN1 has cross-link repair activities that are independent of the Fanconi anemia proteins and that this activity is redundant with the 5′–3′ exonuclease SNM1A. Karyomegaly becomes prominent in kidneys and livers of Fan1-deficient mice with age, and mice develop liver dysfunction. Treatment of Fan1-deficient mice with ICL-inducing agents results in pronounced thymic and bone marrow hypocellularity and the disappearance of c-kit+ cells. Our results provide insight into the mechanism of FAN1 in ICL repair and demonstrate that the Fan1 mouse model effectively recapitulates the pathological features of human FAN1 deficiency. |
| تدمد: | 1549-5477 0890-9369 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::25c07284f743e0ffee0f5e9fcbf9f77bTest https://doi.org/10.1101/gad.276261.115Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....25c07284f743e0ffee0f5e9fcbf9f77b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15495477 08909369 |
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