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Defective replication stress response inhibits lymphomagenesis and impairs lymphocyte reconstitution

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Abstract

DNA replication stress promotes genome instability in cancer. However, the contribution of the replication stress response to the development of malignancies remains unresolved. The DNA replication stress response protein SMARCAL1 stabilizes DNA replication forks and prevents replication fork collapse, a cause of DNA breaks and apoptosis. While the fork regression/remodeling functions of SMARCAL1 have been investigated, its in vivo functions in replication stress and cancer are unclear. Using a gamma radiation (IR)-induced replication stress T-cell lymphoma mouse model, we observed a significant inhibition of lymphomagenesis in mice lacking one or both alleles of Smarcal1. Notably, a quarter of the Smarcal1-deficient mice did not develop tumors. Moreover, hematopoietic stem/progenitor cells (HSPCs) and developing thymocytes in Smarcal1-deficient mice showed increased DNA damage and apoptosis during the proliferation burst following IR and an impaired ability to repopulate the thymus after IR. Additionally, mice lacking Smarcal1 showed significant HSPC defects when challenged to respond to other replication stress stimuli. Thus, our data reveal the critical function of the DNA replication stress response and, specifically, Smarcal1 in hematopoietic cell survival and tumor development. Our results also provide important insight into the immunodeficiency observed in individuals with mutations in SMARCAL1 by suggesting that it is an HSPC defect.

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Acknowledgements

The authors would like to thank Dr Cornelius Boerkoel for providing the Smarcal1+/Δ mice, Carol Bansbach for technical assistance with Figure 1b, Catherine Alford for technical assistance with flow cytometry, the Bioimaging Shared Resource of the Sidney Kimmel Cancer Center, and Dr Sandy Zinkel, Dr Scott Hiebert, and members of the Eischen lab for helpful discussions. This work was supported by F30CA189433 (MVP), T32GM007347 (MVP), Ann Melly Scholarship (MVP), R01CA160432 (CME and DC), and NCI Cancer Center Support Grants P30CA068485 and P30CA056036.

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Correspondence to C M Eischen.

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Puccetti, M., Fischer, M., Arrate, M. et al. Defective replication stress response inhibits lymphomagenesis and impairs lymphocyte reconstitution. Oncogene 36, 2553–2564 (2017). https://doi.org/10.1038/onc.2016.408

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