PRMT5 Regulates DNA Repair by Controlling the Alternative Splicing of Histone-Modifying Enzymes
Autor: | Stephanie Duffort, Stephen D. Nimer, Ramiro E. Verdun, Adnan K. Mookhtiar, Fan Liu, Concepción Martínez, Sarah Greenblatt, Gabriel E. Santiago, Pierre-Jacques Hamard, Na Man, Daniel L. Karl |
---|---|
Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Protein-Arginine N-Methyltransferases DNA Repair DNA repair General Biochemistry Genetics and Molecular Biology Article Lysine Acetyltransferase 5 Histones 03 medical and health sciences Cell Line Tumor Humans KAT5 lcsh:QH301-705.5 biology Cell Death Chemistry Protein arginine methyltransferase 5 Alternative splicing Myeloid leukemia Cell Cycle Checkpoints Lysine Acetyltransferases Cell biology Histone Code Alternative Splicing 030104 developmental biology Histone lcsh:Biology (General) RNA splicing PARP inhibitor biology.protein |
Zdroj: | Cell Reports, Vol 24, Iss 10, Pp 2643-2657 (2018) |
ISSN: | 2211-1247 |
Popis: | Summary: Protein arginine methyltransferase 5 (PRMT5) is overexpressed in many cancer types and is a promising therapeutic target for several of them, including leukemia and lymphoma. However, we and others have reported that PRMT5 is essential for normal physiology. This dependence may become dose limiting in a therapeutic setting, warranting the search for combinatorial approaches. Here, we report that PRMT5 depletion or inhibition impairs homologous recombination (HR) DNA repair, leading to DNA-damage accumulation, p53 activation, cell-cycle arrest, and cell death. PRMT5 symmetrically dimethylates histone and non-histone substrates, including several components of the RNA splicing machinery. We find that PRMT5 depletion or inhibition induces aberrant splicing of the multifunctional histone-modifying and DNA-repair factor TIP60/KAT5, which selectively affects its lysine acetyltransferase activity and leads to impaired HR. As HR deficiency sensitizes cells to PARP inhibitors, we demonstrate here that PRMT5 and PARP inhibitors have synergistic effects on acute myeloid leukemia cells. : Hamard et al. show that PRMT5 regulates DNA-repair efficiency in hematopoietic cells by controlling the alternative splicing of key histone modifying and DNA-repair proteins, including TIP60. PRMT5 depletion or inhibition leads to a defect in DNA-repair pathway choice, which may be exploited therapeutically to target acute leukemia cells. Keywords: hematopoiesis, acute myeloid leukemia, DNA damage and repair, homologous recombination, histone post-translational modifications acetylation, methylation, alternative splicing, PRMT5, PRMT5 inhibitor, Tip60/KAT5, 53BP1, PARP inhibitor |
Databáze: | OpenAIRE |
Externí odkaz: |