MYC and the Control of DNA Replication

Dominguez-Sola, David; Gautier, Jean

doi:10.1101/cshperspect.a014423

Cited by 66 publications

(47 citation statements)

References 198 publications

(238 reference statements)

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“…Upon 4-hydroxytamoxifen (4-OHT) treatment, MYC translocates to the nucleus where it is active and leads to increased accumulation of cells in S-phase, consistent with the known functions of MYC that cause accelerated entry into S phase (Supplementary Fig. 6A–D) (44). We examined the localization of DNA repair proteins to sites of damage, which can be detected as punctate subnuclear foci by immunofluorescence microscopy.…”

Section: Resultssupporting

confidence: 63%

MRE11 Promotes Tumorigenesis by Facilitating Resistance to Oncogene-Induced Replication Stress

et al. 2017

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Hypomorphic mutations in the genes encoding the MRE11/RAD50/NBS1 (MRN) DNA repair complex lead to cancer-prone syndromes. MRN binds DNA double strand breaks where it functions in repair and triggers cell cycle checkpoints via activation of the ataxia-telangiectasia mutated (ATM) kinase. To gain understanding of MRN in cancer, we engineered mice with B lymphocytes lacking MRN, or harboring MRN in which MRE11 lacks nuclease activities. Both forms of MRN deficiency led to hallmarks of cancer, including oncogenic translocations involving c-Myc and the immunoglobulin locus. These pre-neoplastic B lymphocytes did not progress to detectable B lineage lymphoma, even in the absence of p53. Moreover, Mre11 deficiencies prevented tumorigenesis in a mouse model strongly predisposed to spontaneous B cell lymphomas. Our findings indicate that MRN cannot be considered a standard tumor suppressor and instead imply that nuclease activities of MRE11 are required for oncogenesis. Inhibition of MRE11 nuclease activity increased DNA damage and selectively induced apoptosis in cells overexpressing oncogenes, suggesting MRE11 serves an important role in countering oncogene-induced replication stress. Thus, MRE11 may offer a target for cancer therapeutic development. More broadly, our work supports the idea that subtle enhancements of endogenous genome instability can exceed the tolerance of cancer cells and be exploited for therapeutic ends.

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Section: Resultssupporting

confidence: 63%

MRE11 Promotes Tumorigenesis by Facilitating Resistance to Oncogene-Induced Replication Stress

et al. 2017

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“…Indeed, MYC is part of the replication complex (Dominguez-Sola et al 2007;Srinivasan et al 2013;see Dominguez-Sola andGautier 2014 andKuzyk andMai 2014). However, MYC alone cannot cause mitotic cellular division (Felsher et al 2000).…”

Section: Myc As An Initiator Of Tumorigenesismentioning

confidence: 99%

MYC Activation Is a Hallmark of Cancer Initiation and Maintenance

Gabay

Felsher

2014

Cold Spring Harbor Perspectives in Medicine

670

572

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The MYC proto-oncogene has been implicated in the pathogenesis of most types of human tumors. MYC activation alone in many normal cells is restrained from causing tumorigenesis through multiple genetic and epigenetically controlled checkpoint mechanisms, including proliferative arrest, apoptosis, and cellular senescence. When pathologically activated in a permissive epigenetic and/or genetic context, MYC bypasses these mechanisms, enforcing many of the "hallmark" features of cancer, including relentless tumor growth associated with DNA replication and transcription, cellular proliferation and growth, protein synthesis, and altered cellular metabolism. MYC mandates tumor cell fate, by inducing stemness and blocking cellular senescence and differentiation. Additionally, MYC orchestrates changes in the tumor microenvironment, including the activation of angiogenesis and suppression of the host immune response. Provocatively, brief or even partial suppression of MYC back to its physiological levels of activation can result in the restoration of intrinsic checkpoint mechanisms, resulting in acute and sustained tumor regression, associated with tumor cells undergoing proliferative arrest, differentiation, senescence, and apoptosis, as well as remodeling of the tumor microenvironment, recruitment of an immune response, and shutdown of angiogenesis. Hence, tumors appear to be "addicted" to MYC because of both tumor cellintrinsic, cell-autonomous and host-dependent, immune cell-dependent mechanisms. Both the trajectory and persistence of many human cancers require sustained MYC activation. Multiscale mathematical modeling may be useful to predict when tumors will be addicted to MYC. MYC is a hallmark molecular feature of both the initiation and maintenance of tumorigenesis.

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“…MYC was found to directly promote DNA replication by recruiting licensing factors to origins of replication and collaborating with the Werner DNA helicase to accelerate S-phase entry (Dominguez-Sola et al 2007;Robinson et al 2009;Dominguez-Sola and Gautier 2014). Another nontranscriptional activity of MYC derives from the cleavage of full-length MYC protein by calpain protease to remove the NLS and the entire bHLHZ domain (Fig.…”

Section: Myc As a Sensor And Effector Of Cellular Informationmentioning

confidence: 99%

An Overview of MYC and Its Interactome

Conacci‐Sorrell

McFerrin

Eisenman

2014

Cold Spring Harbor Perspectives in Medicine

351

398

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This review is intended to provide a broad outline of the biological and molecular functions of MYC as well as of the larger protein network within which MYC operates. We present a view of MYC as a sensor that integrates multiple cellular signals to mediate a broad transcriptional response controlling many aspects of cell behavior. We also describe the larger transcriptional network linked to MYC with emphasis on the MXD family of MYC antagonists. Last, we discuss evidence that the network has evolved for millions of years, dating back to the emergence of animals.

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MYC and the Control of DNA Replication

Cited by 66 publications

References 198 publications

MRE11 Promotes Tumorigenesis by Facilitating Resistance to Oncogene-Induced Replication Stress

MRE11 Promotes Tumorigenesis by Facilitating Resistance to Oncogene-Induced Replication Stress

MYC Activation Is a Hallmark of Cancer Initiation and Maintenance

An Overview of MYC and Its Interactome

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