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The Conserved ATM Kinase RAG2-S365 Phosphorylation Site Limits Cleavage Events in Individual Cells Independent of Any Repair Defect.

Authors :
Hewitt SL
Wong JB
Lee JH
Nishana M
Chen H
Coussens M
Arnal SM
Blumenberg LM
Roth DB
Paull TT
Skok JA
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.)

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