Lagging strand maturation factor Dna2 is a component of the replication checkpoint initiation machinery

Kumar, Sandeep; Burgers, Peter M.

doi:10.1101/gad.204750.112

Cited by 101 publications

(158 citation statements)

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“…It has been shown that the Mec1 kinase activity can be activated through direct protein-protein interaction with a bipartite Mec1 activation motif in the unstructured Cterminal tails of Dpb11 and Ddc1 Burgers 2008, 2009) and also through the unstructured N- terminal region of Dna2 (Kumar and Burgers 2013). Although our results show that SWI/SNF can directly activate Mec1 independently of the known Mec1 activators such as Dpb11 (Supplemental Fig.…”

Section: Regulating Mec1 Kinase Activity Through the Swi/snf Chromaticontrasting

confidence: 50%

“…A recent study identified Dna2 and Tel1 as additional factors contributing to Mec1 activation in S phase. When these known pathways are eliminated, there is still residual Sphase Rad53 activation (Kumar and Burgers 2013), suggesting that additional factors such as SWI/SNF can contribute to Mec1 activation in S phase. The multiple pathways that regulate S-phase Mec1 activation suggest that the cell requires robust and redundant checkpoint response in S phase, and multiple mechanisms must exist to ensure optimal Mec1 activation (Zou 2013).…”

Section: Swi/snf Specifically Functions In S Phase To Promote Mec1 Acmentioning

confidence: 99%

“…Moreover, topoisomerase-binding protein 1 (TopBP1; Dpb11 in budding yeast), which is recruited by the 9-1-1 complex, can activate ATR directly through protein-protein interactions (Kumagai et al 2006;Mordes et al 2008). Finally, a recent study suggested that yeast Dna2 is used specifically during S phase to stimulate Mec1 kinase (Kumar and Burgers 2013).…”

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confidence: 99%

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Regulation of Mec1 kinase activity by the SWI/SNF chromatin remodeling complex

et al. 2015

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ATP-dependent chromatin remodeling complexes alter chromatin structure through interactions with chromatin substrates such as DNA, histones, and nucleosomes. However, whether chromatin remodeling complexes have the ability to regulate nonchromatin substrates remains unclear. Saccharomyces cerevisiae checkpoint kinase Mec1 (ATR in mammals) is an essential master regulator of genomic integrity. Here we found that the SWI/SNF chromatin remodeling complex is capable of regulating Mec1 kinase activity. In vivo, Mec1 activity is reduced by the deletion of Snf2, the core ATPase subunit of the SWI/SNF complex. SWI/SNF interacts with Mec1, and cross-linking studies revealed that the Snf2 ATPase is the main interaction partner for Mec1. In vitro, SWI/SNF can activate Mec1 kinase activity in the absence of chromatin or known activators such as Dpb11. The subunit requirement of SWI/SNFmediated Mec1 regulation differs from that of SWI/SNF-mediated chromatin remodeling. Functionally, SWI/SNFmediated Mec1 regulation specifically occurs in S phase of the cell cycle. Together, these findings identify a novel regulator of Mec1 kinase activity and suggest that ATP-dependent chromatin remodeling complexes can regulate nonchromatin substrates such as a checkpoint kinase.

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Section: Regulating Mec1 Kinase Activity Through the Swi/snf Chromaticontrasting

confidence: 50%

Section: Swi/snf Specifically Functions In S Phase To Promote Mec1 Acmentioning

confidence: 99%

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Regulation of Mec1 kinase activity by the SWI/SNF chromatin remodeling complex

et al. 2015

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“…In general, the cells require DNA2 for repression of replicative stress. DNA2 can trigger proper intra-S-phase checkpoints, 49 prevent replication fork reversal, 50 and restart replication when forks have already undergone reversal. 51 However, in response to ICL-inducing agents, DNA2 contributes to over-resection of DNA due to an imbalanced hyperactivation of its nuclease activity in response to loss of FancD2 and/or to impairment of the replication fork stabilizer BOD1L.…”

Section: Ganetespib Carboplatin Combinationmentioning

confidence: 99%

Strong antitumor synergy between DNA crosslinking and HSP90 inhibition causes massive premitotic DNA fragmentation in ovarian cancer cells

et al. 2016

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All current regimens for treating ovarian cancer center around carboplatin as standard first line. The HSP90 inhibitor ganetespib is currently being assessed in advanced clinical oncology trials. Thus, we tested the combined effects of ganetespib and carboplatin on a panel of 15 human ovarian cancer lines. Strikingly, the two drugs strongly synergized in cytotoxicity in tumor cells lacking wild-type p53. Mechanistically, ganetespib and carboplatin in combination, but not individually, induced persistent DNA damage causing massive global chromosome fragmentation. Live-cell microscopy revealed chromosome fragmentation occurring to a dramatic degree when cells condensed their chromatin in preparation for mitosis, followed by cell death in mitosis or upon aberrant exit from mitosis. HSP90 inhibition caused the rapid decay of key components of the Fanconi anemia pathway required for repair of carboplatin-induced interstrand crosslinks (ICLs), as well as of cell cycle checkpoint mediators. Overexpressing FancA rescued the DNA damage induced by the drug combination, indicating that FancA is indeed a key client of Hsp90 that enables cancer cell survival in the presence of ICLs. Conversely, depletion of nuclease DNA2 prevented chromosomal fragmentation, pointing to an imbalance of defective repair in the face of uncontrolled nuclease activity as mechanistic basis for the observed premitotic DNA fragmentation. Importantly, the drug combination induced robust antitumor activity in xenograft models, again accompanied with depletion of FancA. In sum, our findings indicate that ganetespib strongly potentiates the antitumor efficacy of carboplatin by causing combined inhibition of DNA repair and cell cycle control mechanisms, thus triggering global chromosome disruption, aberrant mitosis and cell death. 6 This provides a strong rationale for HSP90 inhibitors in cancer therapy 7 and raises the possibility that HSP90 inhibitors can be used in combination with DNAdamaging chemotherapeutics. 8 Ovarian cancer is among the most common gynecological tumor types and carries the worst prognosis. HSP90 is highly expressed in advanced ovarian carcinoma 9 and thus constitutes a potential therapeutic drug target. 10 In support, HSP90 inhibitors were found effective against ovarian cancer in preclinical models, 11-14 alone or in combination with conventional chemotherapy. 15,16 Carboplatin is the key component of all current first-line therapies for ovarian carcinoma. However, while initially often responding with regression, most tumors relapse and develop resistance within less than a year. 17,18 Like other platinum compounds, carboplatin acts by forming crosslinks within DNA. 17 Platinum compounds form intrastrand DNA lesions but also interstrand crosslinks (ICLs) by covalently linking opposite DNA strands. Such ICLs represent major obstacles to the DNA replication fork 19 and are therefore considered the principal toxic lesion of carboplatin's mode of action. The ICLs can only be removed by a sophisticated DNA repair systemthe Fanconi ...

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“…The best known example is TopBP1. In addition, it was recently reported that the essential lagging strand maturation factor Dna2 is a component of the replication checkpoint machinery in yeast (29). Thus, there is growing evidence that replication and checkpoint signaling pathways are more intimately associated than previously thought.…”

Section: Discussionmentioning

confidence: 87%

Direct Role for the Replication Protein Treslin (Ticrr) in the ATR Kinase-mediated Checkpoint Response

Hassan

Lindsey-Boltz

Kemp

et al. 2013

Journal of Biological Chemistry

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Background: Treslin/Ticrr plays an important role in the initiation of DNA replication. Results: Treslin/Ticrr stimulates ATR phosphorylation of Chk1 both in vitro and in vivo. Conclusion: Treslin/Ticrr is a dual replication/checkpoint protein that directly participates in the ATR-mediated checkpoint. Significance: Identification of the essential components of the ATR checkpoint response is crucial for understanding this important signal transduction pathway.

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Lagging strand maturation factor Dna2 is a component of the replication checkpoint initiation machinery

Cited by 101 publications

References 50 publications

Regulation of Mec1 kinase activity by the SWI/SNF chromatin remodeling complex

Regulation of Mec1 kinase activity by the SWI/SNF chromatin remodeling complex

Strong antitumor synergy between DNA crosslinking and HSP90 inhibition causes massive premitotic DNA fragmentation in ovarian cancer cells

Direct Role for the Replication Protein Treslin (Ticrr) in the ATR Kinase-mediated Checkpoint Response

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