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The Conserved ATM Kinase RAG2-S365 Phosphorylation Site Limits Cleavage Events in Individual Cells Independent of Any Repair Defect.
- Source :
-
Cell reports [Cell Rep] 2017 Oct 24; Vol. 21 (4), pp. 979-993. - Publication Year :
- 2017
-
Abstract
- Many DNA lesions associated with lymphoid malignancies are linked to off-target cleavage by the RAG1/2 recombinase. However, off-target cleavage has mostly been analyzed in the context of DNA repair defects, confounding any mechanistic understanding of cleavage deregulation. We identified a conserved SQ phosphorylation site on RAG2 365 to 366 that is involved in feedback control of RAG cleavage. Mutation of serine 365 to a non-phosphorylatable alanine permits bi-allelic and bi-locus RAG-mediated breaks in the same cell, leading to reciprocal translocations. This phenomenon is analogous to the phenotype we described for ATM kinase inactivation. Here, we establish deregulated cleavage itself as a driver of chromosomal instability without the associated repair defect. Intriguingly, a RAG2-S365E phosphomimetic rescues the deregulated cleavage of ATM inactivation, reducing the incidence of reciprocal translocations. These data support a model in which feedback control of cleavage and maintenance of genome stability involves ATM-mediated phosphorylation of RAG2.<br /> (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Amino Acid Motifs
Ataxia Telangiectasia Mutated Proteins metabolism
Conserved Sequence
DNA Repair
DNA-Binding Proteins chemistry
DNA-Binding Proteins genetics
Humans
Lymphocytes metabolism
Mutation
Nuclear Proteins chemistry
Nuclear Proteins genetics
Phosphorylation
Chromosomal Instability
DNA-Binding Proteins metabolism
Nuclear Proteins metabolism
Protein Processing, Post-Translational
Subjects
Details
- Language :
- English
- ISSN :
- 2211-1247
- Volume :
- 21
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 29069605
- Full Text :
- https://doi.org/10.1016/j.celrep.2017.09.084