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The ATM–BID pathway regulates quiescence and survival of haematopoietic stem cells


BID, a BH3-only BCL2 family member, functions in apoptosis as well as the DNA-damage response1. Our previous data demonstrated that BID is an ATM effector acting to induce cell-cycle arrest and inhibition of apoptosis following DNA damage2,3. Here we show that ATM-mediated BID phosphorylation plays an unexpected role in maintaining the quiescence of haematopoietic stem cells (HSCs). Loss of BID phosphorylation leads to escape from quiescence of HSCs, resulting in exhaustion of the HSC pool and a marked reduction of HSC repopulating potential in vivo. We also demonstrate that BID phosphorylation plays a role in protecting HSCs from irradiation, and that regulating both quiescence and survival of HSCs depends on BID’s ability to regulate oxidative stress. Moreover, loss of BID phosphorylation, ATM knockout or exposing mice to irradiation leads to an increase in mitochondrial BID, which correlates with an increase in mitochondrial oxidative stress. These results show that the ATM–BID pathway serves as a critical checkpoint for coupling HSC homeostasis and the DNA-damage stress response to enable long-term regenerative capacity.

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Figure 1: BIDAA mice and haematopoietic stem and progenitor cells are hypersensitive to TBI.
Figure 2: BIDAA HSCs are less quiescent and demonstrate a competitive disadvantage in bone-marrow repopulation.
Figure 3: The quiescence capacity of HSCs depends on the ability of phosphorylated BID to regulate oxidative stress.
Figure 4: Protecting HSCs from irradiation depends on the ability of phosphorylated BID to regulate oxidative stress.
Figure 5: Loss of BID phosphorylation, ATM knockout or exposing mice to irradiation leads to an increase in both mitoBID and mitoROS.


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We are grateful to A. Harmelin, R. Haffner, A. Maizenberg, G. Damari, Y. Chermesh, C. Raanan and N. Nevo for help with the animal studies, and I. Ino, O. Amram and E. Gamil for animal maintenance. We are especially grateful to Y. Shilo (Tel Aviv University) for ATM−/− mice, and to T. Lapidot (Weizmann Institute) for advice and for reading the manuscript. We also thank A. Sharp, E. Ariel and Z. Porat for assistance with flow-cytometric studies and cell sorting and J. Lotem for advice regarding some of the studies. This study was supported in part by the Israel Science Foundation, USA–Israel Binational Science Foundation, German–Israel Foundation, German–Israel Research Program in Cancer Research, Israel Cancer Association, Minerva Stiftung and MDM ICR Research Award. A.G. is the incumbent of the Armour Family Career Development Chair of Cancer Research.

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Authors and Affiliations



M.M. carried out most of the experiments presented in the paper. G.O. carried out some of the initial experiments. H.N. generated the BIDAA mice and carried out the initial characterization of these mice. L.V. carried out the BID−/− and γH2AX studies, and Y.Z. helped with many of the experiments and especially with the subcellular fractionation studies. O.B. carried out the pathology of bone-marrow sections, T.L. was our consultant on HSC biology and S.J. was our main consultant on all the immunology-related studies. M.M. and A.G. planned the projects and wrote the paper. All authors discussed the results and commented on the manuscript.

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Correspondence to Atan Gross.

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Maryanovich, M., Oberkovitz, G., Niv, H. et al. The ATM–BID pathway regulates quiescence and survival of haematopoietic stem cells. Nat Cell Biol 14, 535–541 (2012).

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