Endonuclease G initiates DNA rearrangements at the MLL breakpoint cluster upon replication stress
| Autor: | E Mian, C I Ireno, Cindy Baumann, Lisa Wiesmüller, B Gole |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
DNA Replication
Cancer Research DNA Repair DNA repair ENDOG Ataxia Telangiectasia Mutated Proteins Biology Translocation Genetic chemistry.chemical_compound Aphidicolin Stress Physiological Genetics Histone H2B Humans Molecular Biology Cells Cultured Nucleic Acid Synthesis Inhibitors Recombination Genetic Endodeoxyribonucleases DNA Breaks DNA replication Histone-Lysine N-Methyltransferase Molecular biology Chromatin chemistry Caspases DNA fragmentation Homologous recombination Myeloid-Lymphoid Leukemia Protein DNA HeLa Cells |
| Zdroj: | Oncogene. 34:3391-3401 |
| ISSN: | 1476-5594 0950-9232 |
| Popis: | MLL (myeloid/lymphoid or mixed-lineage leukemia) rearrangements are frequent in therapy-related and childhood acute leukemia, and are associated with poor prognosis. The majority of the rearrangements fall within a 7.3-kb MLL breakpoint cluster region (MLLbcr), particularly in a 0.4-kb hotspot at the intron11-exon12 boundary. The underlying mechanisms are poorly understood, though multiple pathways including early apoptotic signaling, accompanied by high-order DNA fragmentation, have been implicated. We introduced the MLLbcr hotspot in an EGFP-based recombination reporter system and demonstrated enhancement of both spontaneous and genotoxic treatment-induced DNA recombination by the MLLbcr in various human cell types. We identified Endonuclease G (EndoG), an apoptotic nuclease, as an essential factor for MLLbcr-specific DNA recombination after induction of replication stress. We provide evidence for replication stress-induced nuclear accumulation of EndoG, DNA binding by EndoG as well as cleavage of the chromosomal MLLbcr locus in a manner requiring EndoG. We demonstrate additional dependency of MLLbcr breakage on ATM signaling to histone H2B monoubiquitinase RNF20, involved in chromatin relaxation. Altogether our findings provide a novel mechanism underlying MLLbcr destabilization in the cells of origin of leukemogenesis, with replication stress-activated, EndoG-mediated cleavage at the MLLbcr, which may serve resolution of the stalled forks via recombination repair, however, also permits MLL rearrangements. |
| Databáze: | OpenAIRE |
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