Bid protects the mouse hematopoietic system following hydroxyurea-induced replicative stress

Abstract

Hematopoietic stem cells (HSCs) possess long-term self-renewal capacity and multipotent differentiative capacity, to maintain the hematopoietic system. Long-term hematopoietic homeostasis requires effective control of genotoxic damage to maintain HSC function and prevent propagation of deleterious mutations. Here we investigate the role of the BH3-only Bcl-2 family member Bid in the response of murine hematopoietic cells to long-term replicative stress induced by hydroxyurea (HU). The PI3-like serine/threonine kinase, ATR, initiates the DNA damage response (DDR) to replicative stress. The pro-apoptotic Bcl-2 family member, Bid, facilitates this response to replicative stress in hematopoietic cells, but the in vivo role of this DDR function of Bid has not been defined. Surprisingly, we demonstrate that long-term HU treatment expands wild-type myeloid progenitor cells (MPCs) and HSC-enriched Lin À Sca1 þ Kit þ (LSK) cells to maintain bone marrow function as measured by long-term competitive repopulating ability. Bid À / À MPCs demonstrate increased sensitivity to HU and are depleted. Bid À / À LSK cells demonstrate increased mobilization manifest by increased Bromodeoxyuridine (BrdU) incorporation. Bid À / À MPCs and LSK cells are relatively depleted, however, and bone marrow from Bid À / À mice demonstrates decreased long-term competitive repopulating ability in both primary and secondary transplants. We thus describe a survival function of Bid in hematopoiesis in the setting of chronic replicative stress.

Gli1 Protein Regulates the S-phase Checkpoint in Tumor Cells via Bid Protein, and Its Inhibition Sensitizes to DNA Topoisomerase 1 Inhibitors

“…Surprisingly, a substantial decrease in transcript levels of the proapoptotic gene BID (BH3-interacting domain death agonist) was observed in Gli1 knockdown A549 cells (data not shown). Although Bid is well known for proapoptosis signaling, many recent studies confirmed its role in early DDR (50,56). Consistent with these studies, a transient exposure of cancer cells to CPT induced the expression of Bid at both transcript and protein levels in A549 (Figs.…”

The loss of the BH3-only Bcl-2 family member Bid delays T-cell leukemogenesis in Atm−/− mice

“…17,18 In addition, we have demonstrated a role for Bid in the DDR to replicative stress mediated by Atr. 19,21,33 To probe Atmindependent roles for Bid in vivo, we have crossed Bid À / À mice to Atm À / À mice. Surprisingly, we found that loss of Bid increases the latency of leukemogenesis in Atm À / À mice.…”

“…Bid thus functions at the level of the DNA damage sensor complex, and integrates DNA replicative stress signals. [19][20][21] A recent report, using mice harboring Bid mutated in the Atm/Atr phosphorylation sites that has been knocked into the Bid locus, has demonstrated that Atmmediated Bid phosphorylation has a role in protecting HSCs from irradiation and oxidative stress, suggesting the possibility that Bid may have a more general role in sensing stress. 22 An elegant series of experiments has recently demonstrated in the mouse model of lymphomagenesis induced by g irradiation that tumorigenesis is driven by repeated cycles of hematopoietic progenitor cell death, inducing compensatory mobilization of HSC and progenitor cells.…”

“…19 Finally, loss of Bid results in an impaired ability of hematopoietic stem cells (HSC) and progenitor cells to respond to chronic replicative stress induced by hydroxyurea (HU). 20 Mice challenged with repeated doses of HU display decreased HSC and progenitor cells' function. Bid thus functions at the level of the DNA damage sensor complex, and integrates DNA replicative stress signals.…”

Rejuvenating Bi(d)ology

“…Interestingly, in wild-type mice under conditions of repeated replicative stress, the LSK and MPC cell populations are expanded, and bone marrow function is maintained as demonstrated by the ability to compete with unchallenged bone marrow to adequately repopulate lethally irradiated recipient mice. 62 Bid −/− MPCs are more sensitive to replicative stress, resulting in depletion of MPCs following HU. HSCs respond to this loss of progenitor cells by mobilizing to enter the cell cycle.…”