AKT1 Inhibits Homologous Recombination by Inducing Cytoplasmic Retention of BRCA1 and RAD51

Plo, Isabelle; Laulier, Corentin; Gauthier, Laurent; Lebrun, Fabienne; Calvo, Fabien; Lopez, Bernard S.

doi:10.1158/0008-5472.can-08-0861

Cited by 121 publications

(152 citation statements)

References 37 publications

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“…Consistent with our data, both replication stress and centrosome abnormalities have also been reported at early stages of malignancy. Interestingly, HR protects against spontaneous endogenous replication stress, is affected in most familial breast cancers (61), and likely occurs in a high frequency of sporadic cases (62). Therefore, the data presented here shed light on the importance of HR at the molecular interface between replication and mitosis when cells face spontaneous endogenous or low genotoxic stresses that do not trigger cell cycle checkpoints or prevent the cells from entering mitosis.…”

Section: Discussionmentioning

confidence: 75%

Spontaneous slow replication fork progression elicits mitosis alterations in homologous recombination-deficient mammalian cells

Wilhelm

Magdalou

Barascu

et al. 2013

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

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Homologous recombination deficient (HR − ) mammalian cells spontaneously display reduced replication fork (RF) movement and mitotic extra centrosomes. We show here that these cells present a complex mitotic phenotype, including prolonged metaphase arrest, anaphase bridges, and multipolar segregations. We then asked whether the replication and the mitotic phenotypes are interdependent. First, we determined low doses of hydroxyurea that did not affect the cell cycle distribution or activate CHK1 phosphorylation but did slow the replication fork movement of wild-type cells to the same level than in HR − cells. Remarkably, these low hydroxyurea doses generated the same mitotic defects (and to the same extent) in wild-type cells as observed in unchallenged HR − cells. Reciprocally, supplying nucleotide precursors to HR − cells suppressed both their replication deceleration and mitotic extra centrosome phenotypes. Therefore, subtle replication stress that escapes to surveillance pathways and, thus, fails to prevent cells from entering mitosis alters metaphase progression and centrosome number, resulting in multipolar mitosis. Importantly, multipolar mitosis results in global unbalanced chromosome segregation involving the whole genome, even fully replicated chromosomes. These data highlight the crosstalk between chromosome replication and segregation, and the importance of HR at the interface of these two processes for protection against general genome instability.

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Section: Discussionmentioning

confidence: 75%

Spontaneous slow replication fork progression elicits mitosis alterations in homologous recombination-deficient mammalian cells

Wilhelm

Magdalou

Barascu

et al. 2013

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

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“…In contrast, in human fibroblasts and breast cancer cells, we have recently shown that AKT1 activation results in the cytoplasmic retention of BRCA1 and inhibition of homologous recombination (HR) induced by a double-strand break (DSB) targeted into the HR substrate (Plo et al, 2008). Importantly, cytoplasmic retention of BRCA1 was strongly correlated with the level of AKT1 activation in sporadic primary breast tumors (Plo et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, AKT1 also regulates BRCA1 on a posttranslational level, as it is able to phosphorylate BRCA1 in vitro and promotes the nuclear translocation of BRCA1 in T47D human breast cancer cells (Altiok et al, 1999;Miralem and Avraham, 2003;Hinton et al, 2007). In contrast, in human fibroblasts and breast cancer cells, we have recently shown that AKT1 activation results in the cytoplasmic retention of BRCA1 and inhibition of homologous recombination (HR) induced by a double-strand break (DSB) targeted into the HR substrate (Plo et al, 2008). Importantly, cytoplasmic retention of BRCA1 was strongly correlated with the level of AKT1 activation in sporadic primary breast tumors (Plo et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

AKT1 represses gene conversion induced by different genotoxic stresses and induces supernumerary centrosomes and aneuploidy in hamster ovary cells

Plo

Lopez

2009

Oncogene

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The oncogenic kinase AKT1 is frequently overexpressed or activated in sporadic breast and ovarian cancers. In human breast tumors, we have previously shown that AKT1 represses homologous recombination (HR) induced by one double-strand break (DSB). To further analyze the impact of AKT1 on HR, we ectopically expressed wildtype or mutant forms of AKT1 in a hamster ovary cell line containing an intrachromosomal substrate for monitoring HR. In this cell line, AKT1 repressed HR induced by different genotoxic stresses including ionizing radiation, UV-C and one single DSB introduced into the intrachromosomal substrate. Consistently, AKT1 disrupted RAD51 foci formation, showing that AKT1 specifically affects gene conversion. Concomitantly, AKT1 represses both BRCA1 foci formation and HR stimulation resulting from BRCA1 overexpression, showing that AKT1 affects BRCA1-mediated HR functions, also in another species (hamster) and in another type of cell tissue (ovary cells). Finally, consistent with the HR defects, active AKT1 expression induces supernumerary centrosomes and aneuploidy. In addition to its impact on cell proliferation and apoptosis, the present data propose a novel oncogenic function for AKT1, by producing genomic instability as a consequence of HR repression.

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“…The homologous recombination DNA repair proteins BRCA1 and RAD51 have also been shown to be functionally inactivated because of cytoplasmic sequestration following PI3K-AKT pathway activation ( 20 ). Cytoplasmic localization of BRCA1 has been observed in 60% of primary invasive ductal breast cancers, with a high correlation between cytoplasmic BRCA1 localization and AKT1 activity (based on increased levels of phosphorylated AKT1) in the tumors ( 20 ).…”

Section: Reviewmentioning

confidence: 99%

“…Cytoplasmic localization of BRCA1 has been observed in 60% of primary invasive ductal breast cancers, with a high correlation between cytoplasmic BRCA1 localization and AKT1 activity (based on increased levels of phosphorylated AKT1) in the tumors ( 20 ). The exact mechanism of AKT1-induced cytoplasmic sequestration of BRCA1 is currently unknown, but nuclear export of BRCA1 via the XPO1 pathway has previously been described following DNA damage caused by ionizing radiation ( 53 ), and XPO1 has also been implicated in the regulation of BRCA1 centrosomal localization, thus suggesting that AKT-induced nuclear export of BRCA1 may be XPO1 mediated ( 54 ).…”

Section: Reviewmentioning

confidence: 99%

Promising SINEs for Embargoing Nuclear–Cytoplasmic Export as an Anticancer Strategy

et al. 2014

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In cancer cells, the nuclear-cytoplasmic transport machinery is frequently disrupted, resulting in mislocalization and loss of function for many key regulatory proteins. In this review, the mechanisms by which tumor cells co-opt the nuclear transport machinery to facilitate carcinogenesis, cell survival, drug resistance, and tumor progression will be elucidated, with a particular focus on the role of the nuclear-cytoplasmic export protein. The recent development of a new generation of selective inhibitors of nuclear export (XPO1 antagonists) and how these novel anticancer drugs may bring us closer to the implementation of this therapeutic strategy in the clinic will be discussed. Signifi cance:The nuclear transport mechanism is dysregulated in many malignancies and is associated with dysfunction of many regulatory proteins. Targeting this mechanism as an anticancer strategy has been compelling, and novel agents that selectively inhibit the nuclear export pathway have demonstrated preliminary evidence of clinical effi cacy with an acceptable safety profi le. Cancer Discov; 4(5); 527-37.

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AKT1 Inhibits Homologous Recombination by Inducing Cytoplasmic Retention of BRCA1 and RAD51

Cited by 121 publications

References 37 publications

Spontaneous slow replication fork progression elicits mitosis alterations in homologous recombination-deficient mammalian cells

Spontaneous slow replication fork progression elicits mitosis alterations in homologous recombination-deficient mammalian cells

AKT1 represses gene conversion induced by different genotoxic stresses and induces supernumerary centrosomes and aneuploidy in hamster ovary cells

Promising SINEs for Embargoing Nuclear–Cytoplasmic Export as an Anticancer Strategy

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