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

Publication date: 24 October 2017
Source:Cell Reports, Volume 21, Issue 4
Author(s): Susannah L. Hewitt, Jason B. Wong, Ji-Hoon Lee, Mayilaadumveettil Nishana, Hongxi Chen, Marc Coussens, Suzzette M. Arnal, Lili M. Blumenberg, David B. Roth, Tanya T. Paull, Jane A. Skok
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.

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Teaser

DNA lesions associated with lymphoid malignancies are linked to off-target cleavage by the RAG1/2 recombinase. Off-target RAG cleavage has only been analyzed in the context of DNA repair defects. Here, Hewitt et al. identify a phosphorylation site on RAG2 that controls RAG cleavage to maintain genome stability independent of a repair defect.


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