Aberrant RNA methylation triggers recruitment of an alkylation repair complex.
AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase
/ genetics
Cell Nucleus
/ enzymology
DNA Helicases
/ genetics
DNA Methylation
DNA-Binding Proteins
/ genetics
HEK293 Cells
HeLa Cells
Humans
Methylation
Neoplasms
/ enzymology
Nuclear Proteins
/ genetics
R-Loop Structures
RNA Processing, Post-Transcriptional
RNA, Neoplasm
/ genetics
Spliceosomes
/ genetics
Transcription, Genetic
Ubiquitination
ASCC
E3 ligase
RNA methylation
RNF113A
alkylation
genome stability
transcription
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
21 10 2021
21 10 2021
Historique:
received:
03
01
2021
revised:
18
07
2021
accepted:
21
09
2021
entrez:
23
10
2021
pubmed:
24
10
2021
medline:
29
12
2021
Statut:
ppublish
Résumé
Central to genotoxic responses is their ability to sense highly specific signals to activate the appropriate repair response. We previously reported that the activation of the ASCC-ALKBH3 repair pathway is exquisitely specific to alkylation damage in human cells. Yet the mechanistic basis for the selectivity of this pathway was not immediately obvious. Here, we demonstrate that RNA but not DNA alkylation is the initiating signal for this process. Aberrantly methylated RNA is sufficient to recruit ASCC, while an RNA dealkylase suppresses ASCC recruitment during chemical alkylation. In turn, recruitment of ASCC during alkylation damage, which is mediated by the E3 ubiquitin ligase RNF113A, suppresses transcription and R-loop formation. We further show that alkylated pre-mRNA is sufficient to activate RNF113A E3 ligase in vitro in a manner dependent on its RNA binding Zn-finger domain. Together, our work identifies an unexpected role for RNA damage in eliciting a specific response to genotoxins.
Identifiants
pubmed: 34686315
pii: S1097-2765(21)00777-2
doi: 10.1016/j.molcel.2021.09.024
pmc: PMC8931856
mid: NIHMS1749490
pii:
doi:
Substances chimiques
ASCC2 protein, human
0
DNA-Binding Proteins
0
Nuclear Proteins
0
RNA, Neoplasm
0
RNF113A protein, human
0
ALKBH3 protein, human
EC 1.14.11.-
AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase
EC 1.14.11.-
ASCC3 protein, human
EC 3.6.1.-
DNA Helicases
EC 3.6.4.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
4228-4242.e8Subventions
Organisme : NCI NIH HHS
ID : R01 CA248526
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA193318
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA092584
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA227001
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA237263
Pays : United States
Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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