Ubiquitylation of MYC couples transcription elongation with double-strand break repair at active promoters.
ATPases Associated with Diverse Cellular Activities
/ genetics
Cell Line, Tumor
DNA Breaks, Double-Stranded
DNA Repair
Histones
/ genetics
Humans
Promoter Regions, Genetic
Proto-Oncogene Proteins c-myc
/ genetics
RNA Polymerase II
/ genetics
Transcription Elongation, Genetic
Tumor Suppressor Proteins
/ genetics
Ubiquitin-Protein Ligases
/ genetics
Ubiquitination
E3 ligase
HUWE1
MYC
PAF1c
RNAPII
double-strand break repair
histone H2B
ubiquitylation
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
18 02 2021
18 02 2021
Historique:
received:
02
05
2020
revised:
14
10
2020
accepted:
16
12
2020
pubmed:
17
1
2021
medline:
3
3
2021
entrez:
16
1
2021
Statut:
ppublish
Résumé
The MYC oncoprotein globally affects the function of RNA polymerase II (RNAPII). The ability of MYC to promote transcription elongation depends on its ubiquitylation. Here, we show that MYC and PAF1c (polymerase II-associated factor 1 complex) interact directly and mutually enhance each other's association with active promoters. PAF1c is rapidly transferred from MYC onto RNAPII. This transfer is driven by the HUWE1 ubiquitin ligase and is required for MYC-dependent transcription elongation. MYC and HUWE1 promote histone H2B ubiquitylation, which alters chromatin structure both for transcription elongation and double-strand break repair. Consistently, MYC suppresses double-strand break accumulation in active genes in a strictly PAF1c-dependent manner. Depletion of PAF1c causes transcription-dependent accumulation of double-strand breaks, despite widespread repair-associated DNA synthesis. Our data show that the transfer of PAF1c from MYC onto RNAPII efficiently couples transcription elongation with double-strand break repair to maintain the genomic integrity of MYC-driven tumor cells.
Identifiants
pubmed: 33453168
pii: S1097-2765(20)30956-4
doi: 10.1016/j.molcel.2020.12.035
pmc: PMC7611325
mid: EMS129538
pii:
doi:
Substances chimiques
Histones
0
MYC protein, human
0
Proto-Oncogene Proteins c-myc
0
Tumor Suppressor Proteins
0
HUWE1 protein, human
EC 2.3.2.26
Ubiquitin-Protein Ligases
EC 2.3.2.27
RNA Polymerase II
EC 2.7.7.-
ATPases Associated with Diverse Cellular Activities
EC 3.6.4.-
PEX6 protein, human
EC 3.6.4.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
830-844.e13Subventions
Organisme : European Research Council
ID : 669771
Pays : International
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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