BID Binds to Replication Protein A and Stimulates ATR Function following Replicative Stress

Liu, Yang; Vaithiyalingam, Sivaraja; Shi, Qiong; Chazin, Walter J.; Zinkel, Sandra S.

doi:10.1128/mcb.05737-11

Cited by 25 publications

(22 citation statements)

References 64 publications

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“…26 The apoptotic function of Bid is predominantly mediated by its caspasecleavage sites 21,22 and BH3 domain, 38 while Bid executes its function in the DNA damage signaling pathways by its Atm/Atr phosphorylation sites 26,37 its unique Helix 4 and RPA-interacting domains. 19,39 Bid À / À mice spontaneously develop chronic myelomonocytic leukemia (CMML) and the tumor cells display chromosomal aberrations. 20 It is likely that both the apoptotic and DNA damage function of Bid work synergistically to maintain hematopoiesis.…”

Section: Discussionmentioning

confidence: 99%

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

2012

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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.

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Section: Discussionmentioning

confidence: 99%

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

2012

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

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“…17 Furthermore, Bid associates with members of the DNA damage sensor complex, Atrip, the obligate Atr-binding partner, and Replication protein A, and mediates the formation and/or stability of the DNA damage sensor complex. 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.…”

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

et al. 2013

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Multicellular organisms maintain genomic integrity and resist tumorigenesis through a tightly regulated DNA damage response (DDR) that prevents propagation of deleterious mutations either through DNA repair or programmed cell death. An impaired DDR leads to tumorigenesis that is accelerated when programmed cell death is prevented. Loss of the ATM (ataxia telangiectasia mutated)-mediated DDR in mice results in T-cell leukemia driven by accumulation of DNA damage accrued during normal T-cell development. Pro-apoptotic BH3-only Bid is a substrate of Atm, and Bid phosphorylation is required for proper cell cycle checkpoint control and regulation of hematopoietic function. In this report, we demonstrate that, surprisingly, loss of Bid increases the latency of leukemogenesis in Atm À / À mice. Bid À / À Atm À / À mice display impaired checkpoint control and increased cell death of DN3 thymocytes. Loss of Bid thus inhibits T-cell tumorigenesis by increasing clearance of damaged cells, and preventing propagation of deleterious mutations.

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“…BCL-2 family members have been reported to affect DNA damage repair (8)(9)(10), and MCL-1 depletion can decrease Chk1 phosphorylation and increase phosphorylated H2AX (␥-H2AX) in etoposide-treated cells (11). Moreover, MCL-1 has also been shown to interact with several DNA damage response (DDR) proteins, including ␥-H2AX, NBS1, and Ku70 (10,12,13), but the molecular details as to how MCL-1 may regulate DNA double-strand break (DSB) repair have not been established.…”

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MCL-1 Depletion Impairs DNA Double-Strand Break Repair and Reinitiation of Stalled DNA Replication Forks

Mattoo

Pandita

Chakraborty

et al. 2017

Molecular and Cellular Biology

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Myeloid cell leukemia 1 (MCL-1) is a prosurvival BCL-2 protein family member highly expressed in hematopoietic stem cells (HSCs) and regulated by growth factor signals that manifest antiapoptotic activity. Here we report that depletion of MCL-1 but not its isoform MCL-1S increases genomic instability and cell sensitivity to ionizing radiation (IR)-induced death. MCL-1 association with genomic DNA increased postirradiation, and the protein colocalized with 53BP1 foci. Postirradiation, MCL-1-depleted cells exhibited decreased ␥-H2AX foci, decreased phosphorylation of ATR, and higher levels of residual 53BP1 and RIF1 foci, suggesting that DNA double-strand break (DSB) repair by homologous recombination (HR) was compromised. Consistent with this model, MCL-1-depleted cells had a reduced frequency of IRinduced BRCA1, RPA, and Rad51 focus formation, decreased DNA end resection, and decreased HR repair in the DR-GFP DSB repair model. Similarly, after HU induction of stalled replication forks in MCL-1-depleted cells, there was a decreased ability to subsequently restart DNA synthesis, which is normally dependent upon HRmediated resolution of collapsed forks. Therefore, the present data support a model whereby MCL-1 depletion increases 53BP1 and RIF1 colocalization at DSBs, which inhibits BRCA1 recruitment, and sensitizes cells to DSBs from IR or stalled replication forks that require HR for repair.KEYWORDS MCL-1, BCL-2, HR, ICL, apoptosis, 53BP1, DSB repair M CL-1 is a member of the prosurvival BCL-2 family and plays an important role in the regulation of the intrinsic or mitochondrial apoptotic pathway by inhibiting both BH3-only proteins and the proapoptotic proteins (1-3). MCL-1 is mainly located at the outer mitochondrial membrane and inhibits the progression of apoptosis by sequestering executioner proapoptotic proteins BAK and BAX, which are capable of inducing pore formation in the mitochondrial membrane. The subsequent release of cytochrome c into the cytoplasm activates caspases which are responsible for the majority of the macromolecular degradation observed during apoptosis (3). Suppression of BAK and BAX polymerization by MCL-1 is prevented either by MCL-1 degradation or by saturating and inhibiting the MCL-1 binding sites on BAK/BAX with BH3 proteins or mimetics.Under normal growth conditions, MCL-1 is important for mouse embryonic survival (4) and critical for the survival of neutrophils, lymphocytes, hematopoietic stem cells, and neurons (5). MCL-1 overexpression is the hallmark of several cancers, including hematological malignancies as well as solid tumors. Elevated cellular MCL-1 expression correlates with resistance to drug toxicity and ionizing radiation (IR), whereas its inhibition sensitizes cells to both. The BCL-2 family of proteins is characterized by the presence of BCL-2 homology (BH) domains (1, 2). The MCL-1 protein itself is unique among BCL-2 members in also containing multiple N-terminal PEST motifs in addition to BH1, BH2, BH3, and C-terminal transmembrane (TM) domains. PEST is ...

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BID Binds to Replication Protein A and Stimulates ATR Function following Replicative Stress

Cited by 25 publications

References 64 publications

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

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

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

MCL-1 Depletion Impairs DNA Double-Strand Break Repair and Reinitiation of Stalled DNA Replication Forks

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