53BP1-mediated recruitment of RASSF1A to ribosomal DNA breaks promotes local ATM signaling.
Ataxia Telangiectasia Mutated Proteins
/ genetics
DNA Breaks, Double-Stranded
DNA Damage
DNA Repair
DNA, Ribosomal
/ genetics
DNA-Binding Proteins
/ genetics
Genomic Instability
Humans
Phosphorylation
Signal Transduction
/ genetics
Tumor Suppressor Proteins
/ metabolism
Tumor Suppressor p53-Binding Protein 1
/ genetics
53BP1
ATM
DNA damage response
RASSF1A
nucleolus
Journal
EMBO reports
ISSN: 1469-3178
Titre abrégé: EMBO Rep
Pays: England
ID NLM: 100963049
Informations de publication
Date de publication:
03 08 2022
03 08 2022
Historique:
revised:
30
05
2022
received:
09
12
2021
accepted:
03
06
2022
pubmed:
28
6
2022
medline:
5
8
2022
entrez:
27
6
2022
Statut:
ppublish
Résumé
DNA lesions occur across the genome and constitute a threat to cell viability; however, damage at specific genomic loci has a relatively greater impact on overall genome stability. The ribosomal RNA gene repeats (rDNA) are emerging fragile sites. Recent progress in understanding how the rDNA damage response is organized has highlighted a key role of adaptor proteins. Here, we show that the scaffold tumor suppressor RASSF1A is recruited to rDNA breaks. RASSF1A recruitment to double-strand breaks is mediated by 53BP1 and depends on RASSF1A phosphorylation at Serine 131 by ATM kinase. Employing targeted rDNA damage, we uncover that RASSF1A recruitment promotes local ATM signaling. RASSF1A silencing, a common epigenetic event during malignant transformation, results in persistent breaks, rDNA copy number alterations and decreased cell viability. Overall, we identify a novel role for RASSF1A at rDNA break sites, provide mechanistic insight into how the DNA damage response is organized in a chromatin context, and provide further evidence for how silencing of the RASSF1A tumor suppressor contributes to genome instability.
Identifiants
pubmed: 35758159
doi: 10.15252/embr.202154483
pmc: PMC9346497
doi:
Substances chimiques
DNA, Ribosomal
0
DNA-Binding Proteins
0
Tumor Suppressor Proteins
0
Tumor Suppressor p53-Binding Protein 1
0
ATM protein, human
EC 2.7.11.1
Ataxia Telangiectasia Mutated Proteins
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e54483Informations de copyright
© 2022 The Authors. Published under the terms of the CC BY NC ND 4.0 license.
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