An ATR- and BRCA1-Mediated Fanconi Anemia Pathway Is Required for Activating the G<sub>2</sub>/M Checkpoint and DNA Damage Repair upon Rereplication

Zhu, Wenge; Dutta, Anindya

doi:10.1128/mcb.02141-05

Cited by 79 publications

(106 citation statements)

References 52 publications

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“…This Chk2-and p53-independent cell death pathway is probably similar to the one that mediates a delayed cell death in chk2 and p53 mutants after ionizing radiation, although further experiments will be required to define this pathway (Wichmann et al 2006). Our results in Drosophila are similar to those from human cells in culture, in which Cdt1 misexpression induces p53-dependent apoptosis, suggesting that the rereplication checkpoint response is conserved (Vaziri et al 2003;Zhu and Dutta 2006).…”

Section: Rereplication Induces Apoptosis In Drosophilasupporting

confidence: 77%

“…In addition, multicellular eukaryotes express another important inhibitor of pre-RC reassembly, Geminin, which binds Cdt1 and prevents it from reloading the MCM complex after origins initiate (McGarry and Kirschner 1998;Wohlschlegel et al 2000;Tada 2007). In human cells, increased Cdt1 results in DNA rereplication and DNA damage that activates a G2/M checkpoint arrest, mediated by the Fanconia anemia checkpoint proteins (FANC), or apoptosis mediated by p53 (Melixetian et al 2004;Zhu et al 2004;Zhu and Dutta 2006). Cdt1 is up-regulated in several human cancers, and misexpression of Cdt1 in T cells of p53 mutant mice results in aneuploidy and a highly penetrant lymphoma, consistent with other evidence that the DNA damage caused by rereplication can lead to genome instability and oncogenesis if checkpoints fail (Hook et al 2007).…”

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confidence: 99%

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Endocycling cells do not apoptose in response to DNA rereplication genotoxic stress

Mehrotra¹,

Maqbool²,

Kolpakas³

et al. 2008

Genes Dev.

130

155

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Initiation of DNA replication at origins more than once per cell cycle results in rereplication and has been implicated in cancer. Here we use Drosophila to examine the checkpoint responses to rereplication in a developmental context. We find that increased Double-parked (Dup), the Drosophila ortholog of Cdt1, results in rereplication and DNA damage. In most cells, this rereplication triggers caspase activation and apoptotic cell death mediated by both p53-dependent and -independent pathways. Elevated Dup also caused DNA damage in endocycling cells, which switch to a G/S cycle during normal development, indicating that rereplication and the endocycling DNA reduplication program are distinct processes. Unexpectedly, however, endocycling cells do not apoptose regardless of tissue type. Our combined evidence suggests that endocycling apoptosis is repressed in part because proapoptotic gene promoters are silenced. Normal endocycling cells had DNA lesions near heterochromatin, which increased after rereplication, explaining why endocycling cells must constantly repress the genotoxic apoptotic response. Our results reveal a novel regulation of apoptosis in development and new insights into the little-understood endocycle. Similar mechanisms may operate during vertebrate development, with implications for cancer predisposition in certain tissues.[Keywords: DNA replication; DNA damage; endocycle; checkpoint; apoptosis] Supplemental material is available at http://www.genesdev.org. The timely duplication of the genome during S phase of every cell division cycle requires that DNA replication initiate from thousands of origins. If too few origins initiate, replication forks can collapse, resulting in DNA damage and incomplete replication of the genome. Initiation of DNA replication from origins more than once per cell cycle, however, results in "rereplication" and subsequent DNA damage (Arias and Walter 2007). In recent years, it has become increasingly apparent that problems with DNA replication are common in premalignant cells, with subsequent checkpoint defects leading to genome instability and cancer (Dutta 2007). It remains unclear, however, whether all cells in development are equivalent with respect to their regulation of DNA replication and checkpoint responses. Here, we use Drosophila to investigate the checkpoint responses to rereplication in a developmental context. Two important steps in the cell cycle regulation of DNA replication are the assembly and activation of a prereplicative complex (pre-RC) (Sivaprasad et al. 2006). The pre-RC assembles onto origins in early G1 and is subsequently activated in S phase. During pre-RC assembly, the hexameric origin recognition complex (ORC) serves as a scaffold for origin association of Cdc6 and Cdt1, which are both required to load the hexameric minichromosome maintenance complex (MCM), the replicative helicase (Randell et al. 2006;Sivaprasad et al. 2006). Once the MCM complex is tightly bound, the origins are considered to be "licensed" and competent to initiate replic...

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Section: Rereplication Induces Apoptosis In Drosophilasupporting

confidence: 77%

mentioning

confidence: 99%

Endocycling cells do not apoptose in response to DNA rereplication genotoxic stress

Mehrotra¹,

Maqbool²,

Kolpakas³

et al. 2008

Genes Dev.

130

155

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“…Mitotic catastrophe is a term used to describe these failures in mitosis, reported previously in literature (3, 12 -15). Accumulating evidence has implicated Brca1 as a key regulator of the DNA damage checkpoint response, the S and G 2 -M checkpoint (16). Studies by Yarden et al (17) show that Brca1 is necessary to activate chek1-induced DNA damage G 2 -M arrest.…”

Section: Introductionmentioning

confidence: 99%

Mitotic catastrophe cell death induced by heat shock protein 90 inhibitor in BRCA1-deficient breast cancer cell lines

Zając¹,

Moneo

Carnero

et al. 2008

Molecular Cancer Therapeutics

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Heat shock protein 90 (Hsp90) is a molecular chaperone involved in folding, assembly, maturation, and stabilization of the client proteins that regulate survival of malignant cells. As previous reports correlate high Hsp90 expression with decreased survival in breast cancer, Hsp90 may be a favorable target for investigational therapy in breast cancer. In our study, we have examined the response of a panel of both BRCA1-null (UACC 3199, HCC 1937, and MBA-MD-436) and BRCA1-wt breast cancer cell lines (MCF-7, MBA-MD-157, and Hs578T) to determine the proteins governing response to Hsp90 inhibitor 17-allyloamino-17-demethoxy-geldanamycin. On treatment with the drug, cells arrested at G 2 -M phase and entered aberrant mitosis in a BRCA1-dependent manner. Failure to arrest the cells at or before mitosis resulted in formation of micronucleated cells, aberrant segregation of chromosomes, microtubule misalignment, and multicentrosomes, leading in eventual mitotic catastrophe cell death. Our observations show that BRCA1 mediates G 2 -M transition mainly through chek1 on 17-allyloamino-17-demethoxy-geldanamycin treatment.

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“…Even in the absence of exogenous DNA-damaging agents, deregulated expression of CDT1 causes profound cell cycle defects. Overexpression of CDT1 or the depletion of geminin causes overt rereplication (as evidenced by >4N cells), DNA damage, and the subsequent activation of a prolonged G2/M checkpoint (Vaziri et al 2003;Melixetian et al 2004;Zhu and Dutta 2006).…”

mentioning

confidence: 99%

“…The second pathway requires FANC proteins (FANC-C and FANC-D2) and leads to the downregulation of active CyclinB/CDC2 kinase through unknown mechanisms (Freie et al 2004). Molecular studies have demonstrated that rereplication triggers prolonged G2 arrest through activation of the p53 or FANC pathways (Vaziri et al 2003;Zhu and Dutta 2006).…”

mentioning

confidence: 99%

DTL/CDT2 is essential for both CDT1 regulation and the early G2/M checkpoint

Sansam¹,

Shepard²,

Lai³

et al. 2006

Genes Dev.

151

150

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Checkpoint genes maintain genomic stability by arresting cells after DNA damage. Many of these genes also control cell cycle events in unperturbed cells. By conducting a screen for checkpoint genes in zebrafish, we found that dtl/cdt2 is an essential component of the early, radiation-induced G2/M checkpoint. We subsequently found that dtl/cdt2 is required for normal cell cycle control, primarily to prevent rereplication. Both the checkpoint and replication roles are conserved in human DTL. Our data indicate that the rereplication reflects a requirement for DTL in regulating CDT1, a protein required for prereplication complex formation. CDT1 is degraded in S phase to prevent rereplication, and following DNA damage to prevent origin firing. We show that DTL associates with the CUL4-DDB1 E3 ubiquitin ligase and is required for CDT1 down-regulation in unperturbed cells and following DNA damage. The cell cycle defects of Dtl-deficient zebrafish are suppressed by reducing Cdt1 levels. In contrast, the early G2/M checkpoint defect appears to be Cdt1-independent. Thus, DTL promotes genomic stability through two distinct mechanisms. First, it is an essential component of the CUL4-DDB1 complex that controls CDT1 levels, thereby preventing rereplication. Second, it is required for the early G2/M checkpoint.

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An ATR- and BRCA1-Mediated Fanconi Anemia Pathway Is Required for Activating the G₂/M Checkpoint and DNA Damage Repair upon Rereplication

Cited by 79 publications

References 52 publications

Endocycling cells do not apoptose in response to DNA rereplication genotoxic stress

Endocycling cells do not apoptose in response to DNA rereplication genotoxic stress

Mitotic catastrophe cell death induced by heat shock protein 90 inhibitor in BRCA1-deficient breast cancer cell lines

DTL/CDT2 is essential for both CDT1 regulation and the early G2/M checkpoint

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An ATR- and BRCA1-Mediated Fanconi Anemia Pathway Is Required for Activating the G2/M Checkpoint and DNA Damage Repair upon Rereplication

Cited by 79 publications

References 52 publications

Endocycling cells do not apoptose in response to DNA rereplication genotoxic stress

Endocycling cells do not apoptose in response to DNA rereplication genotoxic stress

Mitotic catastrophe cell death induced by heat shock protein 90 inhibitor in BRCA1-deficient breast cancer cell lines

DTL/CDT2 is essential for both CDT1 regulation and the early G2/M checkpoint

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An ATR- and BRCA1-Mediated Fanconi Anemia Pathway Is Required for Activating the G₂/M Checkpoint and DNA Damage Repair upon Rereplication