The role of the DNA damage response in zebrafish and cellular models of Diamond Blackfan anemia
Ribosomal biogenesis involves the processing of pre-ribosomal RNA. A deficiency of some ribosomal proteins (RPs) impairs processing and causes Diamond Blackfan anemia (DBA), which is associated with anemia, congenital malformations and cancer. p53 mediates many features of DBA, but the mechanism of...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
The Company of Biologists
2014-07-01
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| Series: | Disease Models & Mechanisms |
| Subjects: | |
| Online Access: | http://dmm.biologists.org/content/7/7/895 |
| _version_ | 1818421574162710528 |
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| author | Nadia Danilova Elena Bibikova Todd M. Covey David Nathanson Elizabeth Dimitrova Yoan Konto Anne Lindgren Bertil Glader Caius G. Radu Kathleen M. Sakamoto Shuo Lin |
| author_facet | Nadia Danilova Elena Bibikova Todd M. Covey David Nathanson Elizabeth Dimitrova Yoan Konto Anne Lindgren Bertil Glader Caius G. Radu Kathleen M. Sakamoto Shuo Lin |
| author_sort | Nadia Danilova |
| collection | DOAJ |
| description | Ribosomal biogenesis involves the processing of pre-ribosomal RNA. A deficiency of some ribosomal proteins (RPs) impairs processing and causes Diamond Blackfan anemia (DBA), which is associated with anemia, congenital malformations and cancer. p53 mediates many features of DBA, but the mechanism of p53 activation remains unclear. Another hallmark of DBA is the upregulation of adenosine deaminase (ADA), indicating changes in nucleotide metabolism. In RP-deficient zebrafish, we found activation of both nucleotide catabolism and biosynthesis, which is consistent with the need to break and replace the faulty ribosomal RNA. We also found upregulation of deoxynucleotide triphosphate (dNTP) synthesis – a typical response to replication stress and DNA damage. Both RP-deficient zebrafish and human hematopoietic cells showed activation of the ATR/ATM-CHK1/CHK2/p53 pathway. Other features of RP deficiency included an imbalanced dNTP pool, ATP depletion and AMPK activation. Replication stress and DNA damage in cultured cells in non-DBA models can be decreased by exogenous nucleosides. Therefore, we treated RP-deficient zebrafish embryos with exogenous nucleosides and observed decreased activation of p53 and AMPK, reduced apoptosis, and rescue of hematopoiesis. Our data suggest that the DNA damage response contributes to p53 activation in cellular and zebrafish models of DBA. Furthermore, the rescue of RP-deficient zebrafish with exogenous nucleosides suggests that nucleoside supplements could be beneficial in the treatment of DBA. |
| first_indexed | 2024-12-14T13:12:31Z |
| format | Article |
| id | doaj.art-e6b5d35ac93c47e1ac3949a478bab856 |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-12-14T13:12:31Z |
| publishDate | 2014-07-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-e6b5d35ac93c47e1ac3949a478bab8562022-12-21T23:00:09ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112014-07-017789590510.1242/dmm.015495015495The role of the DNA damage response in zebrafish and cellular models of Diamond Blackfan anemiaNadia DanilovaElena BibikovaTodd M. CoveyDavid NathansonElizabeth DimitrovaYoan KontoAnne LindgrenBertil GladerCaius G. RaduKathleen M. SakamotoShuo LinRibosomal biogenesis involves the processing of pre-ribosomal RNA. A deficiency of some ribosomal proteins (RPs) impairs processing and causes Diamond Blackfan anemia (DBA), which is associated with anemia, congenital malformations and cancer. p53 mediates many features of DBA, but the mechanism of p53 activation remains unclear. Another hallmark of DBA is the upregulation of adenosine deaminase (ADA), indicating changes in nucleotide metabolism. In RP-deficient zebrafish, we found activation of both nucleotide catabolism and biosynthesis, which is consistent with the need to break and replace the faulty ribosomal RNA. We also found upregulation of deoxynucleotide triphosphate (dNTP) synthesis – a typical response to replication stress and DNA damage. Both RP-deficient zebrafish and human hematopoietic cells showed activation of the ATR/ATM-CHK1/CHK2/p53 pathway. Other features of RP deficiency included an imbalanced dNTP pool, ATP depletion and AMPK activation. Replication stress and DNA damage in cultured cells in non-DBA models can be decreased by exogenous nucleosides. Therefore, we treated RP-deficient zebrafish embryos with exogenous nucleosides and observed decreased activation of p53 and AMPK, reduced apoptosis, and rescue of hematopoiesis. Our data suggest that the DNA damage response contributes to p53 activation in cellular and zebrafish models of DBA. Furthermore, the rescue of RP-deficient zebrafish with exogenous nucleosides suggests that nucleoside supplements could be beneficial in the treatment of DBA.http://dmm.biologists.org/content/7/7/895Ribosomal protein deficiencyRps19Rpl11p53ATRRNRChk1ATPAMPKExogenous nucleosides |
| spellingShingle | Nadia Danilova Elena Bibikova Todd M. Covey David Nathanson Elizabeth Dimitrova Yoan Konto Anne Lindgren Bertil Glader Caius G. Radu Kathleen M. Sakamoto Shuo Lin The role of the DNA damage response in zebrafish and cellular models of Diamond Blackfan anemia Disease Models & Mechanisms Ribosomal protein deficiency Rps19 Rpl11 p53 ATR RNR Chk1 ATP AMPK Exogenous nucleosides |
| title | The role of the DNA damage response in zebrafish and cellular models of Diamond Blackfan anemia |
| title_full | The role of the DNA damage response in zebrafish and cellular models of Diamond Blackfan anemia |
| title_fullStr | The role of the DNA damage response in zebrafish and cellular models of Diamond Blackfan anemia |
| title_full_unstemmed | The role of the DNA damage response in zebrafish and cellular models of Diamond Blackfan anemia |
| title_short | The role of the DNA damage response in zebrafish and cellular models of Diamond Blackfan anemia |
| title_sort | role of the dna damage response in zebrafish and cellular models of diamond blackfan anemia |
| topic | Ribosomal protein deficiency Rps19 Rpl11 p53 ATR RNR Chk1 ATP AMPK Exogenous nucleosides |
| url | http://dmm.biologists.org/content/7/7/895 |
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