Base excision repair proteins couple activation-induced cytidine deaminase and endonuclease G during replication stress-induced MLL destabilization
| Autor: | B Gole, E Mian, Melanie Rall, Lisa Wiesmüller |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
DNA Replication Cancer Research DNA Repair Transcription Genetic ENDOG Cleavage (embryo) 03 medical and health sciences Endonuclease Transcription (biology) Cell Line Tumor Cytidine Deaminase Activation-induced (cytidine) deaminase Humans DNA Breaks Double-Stranded Cells Cultured Endodeoxyribonucleases Leukemia biology Stem Cells DNA replication Hematology Cytidine deaminase Base excision repair Histone-Lysine N-Methyltransferase Hematopoietic Stem Cells Molecular biology 030104 developmental biology Oncology biology.protein K562 Cells Myeloid-Lymphoid Leukemia Protein |
| Zdroj: | Leukemia. 32(1) |
| ISSN: | 1476-5551 |
| Popis: | The breakpoint cluster region of the MLL gene (MLLbcr) is frequently rearranged in therapy-related and infant acute leukaemia, but the destabilizing mechanism is poorly understood. We recently proposed that DNA replication stress results in MLLbcr cleavage via endonuclease G (EndoG) and represents the common denominator of genotoxic therapy-induced MLL destabilization. Here we performed a siRNA screen for new factors involved in replication stress-induced MLL rearrangements employing an enhanced green fluorescent protein-based reporter system. We identified 10 factors acting in line with EndoG in MLLbcr breakage or further downstream in the repair of the MLLbcr breaks, including activation-induced cytidine deaminase (AID), previously proposed to initiate MLLbcr rearrangements in an RNA transcription-dependent mechanism. Further analysis connected AID and EndoG in MLLbcr destabilization via base excision repair (BER) components. We show that replication stress-induced recruitment of EndoG to the MLLbcr and cleavage are AID/BER dependent. Notably, inhibition of the core BER factor Apurinic-apyrimidinic endonuclease 1 protects against MLLbcr cleavage in tumour and human cord blood-derived haematopoietic stem/progenitor cells, harbouring the cells of origin of leukaemia. We propose that off-target binding of AID to the MLLbcr initiates BER-mediated single-stranded DNA cleavage, which causes derailed EndoG activity ultimately resulting in leukaemogenic MLLbcr rearrangements. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink