Rad9 Protects Cells from Topoisomerase Poison-induced Cell Death

Loegering, David A.; Arlander, Sonnet J.H.; Hackbarth, Jennifer S.; Vroman, Benjamin T.; Roos-Mattjus, Pia; Hopkins, Kevin M.; Lieberman, Howard B.; Karnitz, Larry M.; Kaufmann, Scott H.

doi:10.1074/jbc.m313536200

Cited by 38 publications

(42 citation statements)

References 60 publications

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“…G 1 -phase delay is usually characterized by DNA synthesis suppression. However, Loegering et al 48 have shown that short-term caffeine treatment does not affect 3 H-thymidine incorporation in ES cells. To investigate the possibility that caffeine blocks initiation of DNA synthesis in ES cells we treated the cells with caffeine for four and eight hours, then pulsed them with BrdU for 20 min and analyzed by flow cytometry.…”

Section: Atr But Not Atm Kinase Inhibition Induces a S-phase Delay mentioning

confidence: 99%

Inhibition of the ATR/Chk1 Pathway Induces a p38-Dependent S-phase Delay in Mouse ES Cells

Jirmanova

Bulavin²,

Fornace³

2005

Cell Cycle

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Section: Atr But Not Atm Kinase Inhibition Induces a S-phase Delay mentioning

confidence: 99%

Inhibition of the ATR/Chk1 Pathway Induces a p38-Dependent S-phase Delay in Mouse ES Cells

Jirmanova

Bulavin²,

Fornace³

2005

Cell Cycle

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“…Shao et al (38) reported that UCN-01, an inhibitor of Chk1 (39 -41), diminishes the S-phase arrest observed after camptothecin. Subsequent studies detected 9-1-1 clamp loading (42,43) (25,46). Parallel studies in yeast have suggested that deletion of genes encoding 9-1-1 complex subunits, the 9-1-1 clamp loader, or the ATR homolog Mec1 also sensitizes cells to topoisomerase I poisoning (47).…”

mentioning

confidence: 99%

The Role of Checkpoint Kinase 1 in Sensitivity to Topoisomerase I Poisons

Flatten

Dai

Vroman

et al. 2005

Journal of Biological Chemistry

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Agents that target topoisomerase I are widely utilized to treat human cancer. Previous studies have indicated that both the ataxia telangiectasia mutated (ATM)/ checkpoint kinase (Chk) 2 and ATM-and Rad 3-related (ATR)/Chk1 checkpoint pathways are activated after treatment with these agents. The relative contributions of these two pathways to survival of cells after treatment with topoisomerase I poisons are currently unknown. To address this issue, we assessed the roles of ATR, Chk1, ATM, and Chk2 in cells treated with the topoisomerase I poisons camptothecin and 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of irinotecan. Colony forming assays demonstrated that down-regulation of ATR or Chk1 sensitized cells to SN-38 and camptothecin. In contrast, ATM and Chk2 had minimal effect of sensitivity to SN-38 or camptothecin. Additional experiments demonstrated that the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin, which down-regulates Chk1, also sensitized a variety of human carcinoma cell lines to SN-38. Collectively, these results show that the ATR/Chk1 pathway plays a predominant role in the response to topoisomerase I inhibitors in carcinoma cells and identify a potential approach for enhancing the efficacy of these drugs.In response to different types of DNA damage, a number of cell cycle checkpoint pathways are activated. These pathways typically involve detection of damage by one or more DNA damage sensors followed by activation of a series of kinases that regulate cellular responses, including cell cycle arrest and DNA repair (reviewed in Refs. 1 and 2).One of these pathways involves the sequential action of the kinases ATM 1 and Chk2. According to current understanding, DNA double-strand breaks and other changes in chromatin structure lead to autophosphorylation of the ATM homodimer (3), which activates ATM and facilitates phosphorylation of a number of substrates (2, 4), including Chk2. Once activated by phosphorylation on Thr 68 (5), Chk2 then phosphorylates p53, contributing to stabilization of this transcription factor and subsequent expression of the cyclin-dependent kinase inhibitor p21 (1, 2, 6). Chk2 also phosphorylates members of the Cdc25 family, contributing to inhibition (Cdc25C) or degradation (Cdc25A) of these phosphatases and preventing them from activating cyclin-dependent kinase complexes that drive cell cycle progression.A second but related cell cycle checkpoint pathway involves sequential action of the kinases ATR and Chk1. When replication forks stall, regions of single-stranded DNA are produced by continued helicase action (7). The exposed single-stranded DNA is bound by replication protein A (7-10), which facilitates the binding of the ATR-ATRIP complex to chromatin (9, 10). At the same time, the preassembled clamp-like Rad9-Hus1-Rad1 complex (the 9-1-1 complex) (11-13) is loaded onto the chromatin by a clamp loader consisting of Rad17 and the four replication factor C small subunits (14, 15). The chromatin-bound 9-1-1 complex facilitates ATR-mediated phospho...

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“…This result is consistent with the requirement of the Rad9A constitutive phosphorylation sites for IR-induced prolonged G 2 /M arrest (7). Additionally, mutation of all known Rad9A C-terminal phosphorylation sites causes a defect in checkpoint response to UV and hydroxyurea treatment, as well as sensitivity to the Topo II poison etoposide (8,9). Loegering et al (9) demonstrated that cells expressing a Rad9A C-terminal nonphosphorylatable mutant ablated the S phase checkpoint to cytarabine, which is also a catalytic inhibitor of Topo II.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, mutation of all known Rad9A C-terminal phosphorylation sites causes a defect in checkpoint response to UV and hydroxyurea treatment, as well as sensitivity to the Topo II poison etoposide (8,9). Loegering et al (9) demonstrated that cells expressing a Rad9A C-terminal nonphosphorylatable mutant ablated the S phase checkpoint to cytarabine, which is also a catalytic inhibitor of Topo II. Thus, the constitutive phosphorylation sites of Rad9A are indispensable for checkpoint activation when challenged by a variety of genotoxins causing DNA damage and Topo II decatenation inhibition and support a role for Rad9A as a general sensor of genomic instability.…”

Section: Discussionmentioning

confidence: 99%

“…The C terminus of Rad9A extends beyond the sequence homology with proliferating cell nuclear antigen and is thought to regulate the 911 complex through its many phosphorylation sites (6 -8 , and ablation of these sites causes prolonged G 2 /M arrest following ionizing radiation (IR), 2 consistent with an S phase checkpoint defect (6,7). Cells expressing Rad9A mutants lacking all known C-terminal phosphorylation sites are also sensitive to hydroxyurea, ultraviolet radiation (UV), topoisomerase I (Topo I) inhibitors, and topoisomerase II (Topo II) poisons (8,9). Rad9A is also hyperphosphorylated in response to DNA damage by inducible phosphorylation at Ser 272 and at a damage and cell cycle-dependent site that has not yet been defined (6,10).…”

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confidence: 99%

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