TY - JOUR
T1 - PRMT5 Regulates DNA Repair by Controlling the Alternative Splicing of Histone-Modifying Enzymes
AU - Hamard, Pierre Jacques
AU - Santiago, Gabriel E.
AU - Liu, Fan
AU - Karl, Daniel L.
AU - Martinez, Concepcion
AU - Man, Na
AU - Mookhtiar, Adnan K.
AU - Duffort, Stephanie
AU - Greenblatt, Sarah
AU - Verdun, Ramiro E.
AU - Nimer, Stephen D.
N1 - Funding Information:
We are grateful to Bruno Amati for providing the TIP60 antibodies. We thank Luisa Luciani, Guoyan Cheng, Madhavi Tadi, Giovanni Lenguito, and Brett Schrand for technical assistance; and Delphine Prou, Daniel Bilbao, and Gloria Mas Martin for scientific discussions and their critical reading of this manuscript. We thank the Oncogenomics Shared Resource Facility and the Flow Cytometry Shared Resource Facility at Sylvester Comprehensive Cancer Center for technical help and support. This work was supported by funds from Sylvester Comprehensive Cancer Center , grant R01 CA166835 from the National Cancer Institute to S.D.N., and grant R01 GM121595 from the National Institute of General Medical Sciences to R.E.V.
Funding Information:
We are grateful to Bruno Amati for providing the TIP60 antibodies. We thank Luisa Luciani, Guoyan Cheng, Madhavi Tadi, Giovanni Lenguito, and Brett Schrand for technical assistance; and Delphine Prou, Daniel Bilbao, and Gloria Mas Martin for scientific discussions and their critical reading of this manuscript. We thank the Oncogenomics Shared Resource Facility and the Flow Cytometry Shared Resource Facility at Sylvester Comprehensive Cancer Center for technical help and support. This work was supported by funds from Sylvester Comprehensive Cancer Center, grant R01 CA166835 from the National Cancer Institute to S.D.N., and grant R01 GM121595 from the National Institute of General Medical Sciences to R.E.V.
PY - 2018/9/4
Y1 - 2018/9/4
N2 - 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.
AB - 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.
KW - 53BP1
KW - DNA damage and repair
KW - PARP inhibitor
KW - PRMT5
KW - PRMT5 inhibitor
KW - Tip60/KAT5
KW - acute myeloid leukemia
KW - alternative splicing
KW - hematopoiesis
KW - histone post-translational modifications acetylation
KW - homologous recombination
KW - methylation
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UR - http://www.scopus.com/inward/citedby.url?scp=85052651970&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2018.08.002
DO - 10.1016/j.celrep.2018.08.002
M3 - Article
C2 - 30184499
AN - SCOPUS:85052651970
VL - 24
SP - 2643
EP - 2657
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 10
ER -