Functional interaction between BLM helicase and 53BP1 in a Chk1-mediated pathway during S-phase arrest

Sengupta, Sagar; Robles, Ana I.; Linke, Steven P.; Sinogeeva, Natasha I; Zhang, Ran; Pedeux, Rémy; Ward, Irene M.; Celeste, Arkady; Nussenzweig, André; Chen, Junjie; Halazonetis, Thanos D.; Harris, Curtis C.

doi:10.1083/jcb.200405128

Cited by 122 publications

(116 citation statements)

References 39 publications

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“…Additionally, the clonal translocations found in these tumors may have occurred in association with the rapid cellular proliferation (i.e., DNA replication) observed during thymocyte expansion as previously proposed for H2AX Ϫ/Ϫ ͞p53 Ϫ/Ϫ tumors (23,24). Such rapid clonal expansion of 53BP1 Ϫ/Ϫ ͞p53 Ϫ/Ϫ T cells would generate numerous translocation donors and acceptors in S-phase, perhaps through aberrant resolution of stalled replication forks, a structure known to recruit 53BP1 (32).…”

Section: Discussionmentioning

confidence: 97%

“…How this event would operate is unknown, but defects in the putative kinetochore function of 53BP1 could be synergistic with p53 deficiency, resulting in an increased rate of mitotic failure. In addition, because 53BP1 is required for recruiting both BLM and p53 to stalled replication forks (32), defects in this H2AX-independent mechanism could contribute to increased genomic instability and tumorigenesis. In this light, it is interesting to note that 53BP1, like p53 and BLM, displays a ''hyper-rec'' phenotype (33).…”

Section: Discussionmentioning

confidence: 99%

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53BP1 and p53 synergize to suppress genomic instability and lymphomagenesis

Morales

Franco

Murphy

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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p53-binding protein 1 (53BP1) participates in the cellular response to DNA double-stranded breaks where it associates with various DNA repair͞cell cycle factors including the H2AX histone variant. Mice deficient for 53BP1 (53BP1 ؊/؊ ) are sensitive to ionizing radiation and immunodeficient because of impaired Ig heavy chain class switch recombination. Here we show that, as compared with p53 ؊/؊ mice, 53BP1 ؊/؊ ͞p53 ؊/؊ animals more rapidly develop tumors, including T cell lymphomas and, at lower frequency, B lineage lymphomas, sarcomas, and teratomas. In addition, T cells from animals deficient for both 53BP1 and p53 (53BP1 ؊/؊ ͞p53 ؊/؊ ) display elevated levels of genomic instability relative to T cells deficient for either 53BP1 or p53 alone. In contrast to p53 ؊/؊ T cell lymphomas, which routinely display aneuploidy but not translocations, 53BP1 ؊/؊ ͞p53 ؊/؊ thymic lymphomas fall into two distinct cytogenetic categories, with many harboring clonal translocations (40%) and the remainder showing aneuploidy (60%). We propose that 53BP1, in the context of p53 deficiency, suppresses T cell lymphomagenesis through its roles in both cell-cycle checkpoints and double-stranded break repair.thymic lymphoma ͉ aneuploidy ͉ translocations D ouble-stranded break (DSB) repair is essential for genomic stability and tumor suppression. In mammalian cells, DSBs arise through exogenous means such as ionizing radiation, at stalled replication forks, and in the context of two genetically programmed processes that occur in lymphoid cells (1-3). DSBs are repaired by either of two nonmutually exclusive mechanisms: homologous recombination and nonhomologous end joining. During the development of the immune system, both B and T cells assemble the exons that encode Igs and T cell receptor variable regions by means of V(D)J recombination. In addition, mature B cells can express different Ig heavy chain constant regions through a DSB-mediated process known as Ig heavy chain class switch recombination (CSR). The DSBs that initiate V(D)J recombination are generated by the site-specific RAG endonuclease, whereas those that initiate CSR appear to involve the activation-induced deaminase. However, both V(D)J recombination and CSR are completed by nonhomologous end joining. In contrast to V(D)J recombination, CSR requires components of the DNA DSB repair response, including the histone variant H2AX and p53 binding protein 1 (53BP1) (4-7), potentially to juxtapose broken DSBs for nonhomologous end joining (8). Although 53BP1 is required for joining of S regions during CSR, like H2AX, it does not appear to be absolutely required for V(D)J recombination (6, 7), perhaps because of the fact that RAG also mediates synapsis functions (8).53BP1 is phosphorylated in response to ionizing radiation, accumulates at or near sites of DNA damage, and participates in the intra S and G 2 ͞M checkpoints (reviewed in ref. 9). Accumulation of 53BP1 at sites of irradiation-induced foci depends on

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

53BP1 and p53 synergize to suppress genomic instability and lymphomagenesis

Morales

Franco

Murphy

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…Histone H 2 AX has been implicated in the maintenance of genomic stability by participating in the repair of DNA damage (Davalos and Campisi, 2003;Sengupta et al, 2004). The phosphorylation of histone H 2 AX on Ser139 by the ataxia telangiectasia mutated (ATM) and ATR (ATM and Rad 3 related) kinases is an early event observed after the generation of DSBs by ionising radiation or DNA-cross-linking agents (Rogakou et al, 1998;Banath and Olive, 2003).…”

Section: Discussionmentioning

confidence: 99%

Combined modalities of resistance in an oxaliplatin-resistant human gastric cancer cell line with enhanced sensitivity to 5-fluorouracil

Chen

Tsou

et al. 2007

Br J Cancer

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To identify mechanisms underlying oxaliplatin resistance, a subline of the human gastric adenocarcinoma TSGH cell line, S3, was made resistant to oxaliplatin by continuous selection against increasing drug concentrations. Compared with the parental TSGH cells, the S3 subline showed 58-fold resistance to oxaliplatin; it also displayed 11-, 2-, and 4.7-fold resistance to cis-diammine-dichloroplatinum (II) (CDDP), copper sulphate, and arsenic trioxide, respectively. Interestingly, S3 cells were fourfold more susceptible to 5-fluorouracilinduced cytotoxicity due to downregulation of thymidylate synthase. Despite elevated glutathione levels in S3 cells, there was no alteration of resistant phenotype to oxaliplatin or CDDP when cells were co-treated with glutathione-depleting agent, l-buthionine-(S,R)-sulphoximine. Cellular CDDP and oxaliplatin accumulation was decreased in S3 cells. In addition, amounts of oxaliplatin-and CDDP -DNA adducts in S3 cells were about 15 and 40% of those seen with TSGH cells, respectively. Western blot analysis showed increased the expression level of copper transporter ATP7A in S3 cells compared with TSGH cells. Partial reversal of the resistance of S3 cells to oxaliplatin and CDDP was observed by treating cell with ATP7A-targeted siRNA oligonucleotides or P-type ATPaseinhibitor sodium orthovanadate. Besides, host reactivation assay revealed enhanced repair of oxaliplatin-or CDDP-damaged DNA in S3 cells compared with TSGH cells. Together, our results show that the mechanism responsible for oxaliplatin and CDDP resistance in S3 cells is the combination of increased DNA repair and overexpression of ATP7A. Downregulation of thymidylate synthase in S3 cells renders them more susceptible to 5-fluorouracil-induced cytotoxicity. These findings could pave ways for future efforts to overcome oxaliplatin resistance.

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“…p53 was shown to respond to the replication block induced by aphidicolin (Gottifredi et al, 2001;Nayak and Das, 2002) and colocalized with BLM, Rad51 and 53BP1 at the sites of stalled DNA replication fork (Sengupta et al, 2003(Sengupta et al, , 2004. p53 also accumulated during S-phase in Cdc7À/À ES cells with defective replication origin firing (Kim et al, 2002).…”

Section: Introductionmentioning

confidence: 97%

Suppression of replication fork progression in low-dose-specific p53-dependent S-phase DNA damage checkpoint

et al. 2006

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The S-phase DNA damage checkpoint is activated by DNA damage to delay DNA synthesis allowing time to resolve the replication block. We previously discovered the p53-dependent S-phase DNA damage checkpoint in mouse zygotes fertilized with irradiated sperm. Here, we report that the same p53 dependency holds in mouse embryonic fibroblasts (MEFs) at low doses of irradiation. DNA synthesis in p53 wild-type (WT) MEFs was suppressed in a biphasic manner in which a sharp decrease below 2.5 Gy was followed by a more moderate decrease up to 10 Gy. In contrast, p53À/À MEFs exhibited radioresistant DNA synthesis below 2.5 Gy whereas the cells retained the moderate suppression above 5 Gy. DNA fiber analysis revealed that 1 Gy irradiation suppressed replication fork progression in p53 WT MEFs, but not in p53À/À MEFs. Proliferating cell nuclear antigen (PCNA), clamp loader of DNA polymerase, was phosphorylated in WT MEFs after 1 Gy irradiation and redistributed to form foci in the nuclei. In contrast, PCNA was not phosphorylated and dissociated from chromatin in 1 Gy-irradiated p53À/À MEFs. These results demonstrate that the novel low-dosespecific p53-dependent S-phase DNA damage checkpoint is likely to regulate the replication fork movement through phosphorylation of PCNA.

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Functional interaction between BLM helicase and 53BP1 in a Chk1-mediated pathway during S-phase arrest

Cited by 122 publications

References 39 publications

53BP1 and p53 synergize to suppress genomic instability and lymphomagenesis

53BP1 and p53 synergize to suppress genomic instability and lymphomagenesis

Combined modalities of resistance in an oxaliplatin-resistant human gastric cancer cell line with enhanced sensitivity to 5-fluorouracil

Suppression of replication fork progression in low-dose-specific p53-dependent S-phase DNA damage checkpoint

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