Association with Aurora-A Controls N-MYC-Dependent Promoter Escape and Pause Release of RNA Polymerase II during the Cell Cycle

TY - JOUR

T1 - Association with Aurora-A Controls N-MYC-Dependent Promoter Escape and Pause Release of RNA Polymerase II during the Cell Cycle

AU - Büchel, Gabriele

AU - Carstensen, Anne

AU - Mak, Ka-Yan

AU - Roeschert, Isabelle

AU - Leen, Eoin

AU - Sumara, Olga

AU - Hofstetter, Julia

AU - Herold, Steffi

AU - Kalb, Jacqueline

AU - Baluapuri, Apoorva

AU - Poon, Evon

AU - Kwok, Colin

AU - Chesler, Louis

AU - Maric, Hans Michael

AU - Rickman, David S

AU - Wolf, Elmar

AU - Bayliss, Richard

AU - Walz, Susanne

AU - Eilers, Martin

N1 - Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

PY - 2017/12/19

Y1 - 2017/12/19

N2 - MYC proteins bind globally to active promoters and promote transcriptional elongation by RNA polymerase II (Pol II). To identify effector proteins that mediate this function, we performed mass spectrometry on N-MYC complexes in neuroblastoma cells. The analysis shows that N-MYC forms complexes with TFIIIC, TOP2A, and RAD21, a subunit of cohesin. N-MYC and TFIIIC bind to overlapping sites in thousands of Pol II promoters and intergenic regions. TFIIIC promotes association of RAD21 with N-MYC target sites and is required for N-MYC-dependent promoter escape and pause release of Pol II. Aurora-A competes with binding of TFIIIC and RAD21 to N-MYC in vitro and antagonizes association of TOP2A, TFIIIC, and RAD21 with N-MYC during S phase, blocking N-MYC-dependent release of Pol II from the promoter. Inhibition of Aurora-A in S phase restores RAD21 and TFIIIC binding to chromatin and partially restores N-MYC-dependent transcriptional elongation. We propose that complex formation with Aurora-A controls N-MYC function during the cell cycle. Büchel et al. demonstrate that N-MYC forms complexes with TFIIIC, TOP2A, and RAD21. Aurora-A competes with TFIIIC and RAD21 for binding to N-MYC, and Aurora-A displaces the three proteins from N-MYC during S phase. As consequence, N-MYC-dependent pause release is inhibited during S phase, preventing activation of the ATR checkpoint kinase.

AB - MYC proteins bind globally to active promoters and promote transcriptional elongation by RNA polymerase II (Pol II). To identify effector proteins that mediate this function, we performed mass spectrometry on N-MYC complexes in neuroblastoma cells. The analysis shows that N-MYC forms complexes with TFIIIC, TOP2A, and RAD21, a subunit of cohesin. N-MYC and TFIIIC bind to overlapping sites in thousands of Pol II promoters and intergenic regions. TFIIIC promotes association of RAD21 with N-MYC target sites and is required for N-MYC-dependent promoter escape and pause release of Pol II. Aurora-A competes with binding of TFIIIC and RAD21 to N-MYC in vitro and antagonizes association of TOP2A, TFIIIC, and RAD21 with N-MYC during S phase, blocking N-MYC-dependent release of Pol II from the promoter. Inhibition of Aurora-A in S phase restores RAD21 and TFIIIC binding to chromatin and partially restores N-MYC-dependent transcriptional elongation. We propose that complex formation with Aurora-A controls N-MYC function during the cell cycle. Büchel et al. demonstrate that N-MYC forms complexes with TFIIIC, TOP2A, and RAD21. Aurora-A competes with TFIIIC and RAD21 for binding to N-MYC, and Aurora-A displaces the three proteins from N-MYC during S phase. As consequence, N-MYC-dependent pause release is inhibited during S phase, preventing activation of the ATR checkpoint kinase.

KW - Journal Article

U2 - 10.1016/j.celrep.2017.11.090

DO - 10.1016/j.celrep.2017.11.090

M3 - Journal article

C2 - 29262328

SN - 2211-1247

VL - 21

SP - 3483

EP - 3497

JO - Cell Reports

JF - Cell Reports

IS - 12

ER -