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

Plo, Isabelle; Lopez, Bernard S.

doi:10.1038/onc.2009.85

Cited by 22 publications

(21 citation statements)

References 31 publications

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“…Delocalizing BRCA1 and RAD51 to the cytoplasm inhibits the nuclear functions of BRCA1, such as the recruitment to sites of damage after exposure to ionizing radiation and the control of HR. Consistent with the phenotype of cells that are mutated in components of HR, cells overexpressing AKT1 have a higher frequency of supernumerary centrosomes [60]. Furthermore, the AKT1 signaling pathway negatively regulates the expression of BRCA1 mRNA [61].…”

supporting

confidence: 53%

“…More directly related to the questions discussed here, the overexpression of AKT1 has been shown to promote the sequestration of BRCA1 and RAD51 to the cytoplasm [38,60]. This sequestration of BRCA1 and RAD51 to the cytoplasm has been observed both in cultured cell lines and in 60% of sporadic breast cancer tumors, in which it is correlated with the level of AKT1 activation [38].…”

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confidence: 92%

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AKT1/BRCA1 in the control of homologous recombination and genetic stability: the missing link between hereditary and sporadic breast cancers

2010

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AbstrAct:Endogenous replicative stress could be one trigger leading to tumor initiation: indeed, activation of the DNA damage response (DDR), considered the result of replicative stress, is observed in pre-cancerous cells; moreover, in hereditary breast cancers, almost all of the genes affected relate to the DDR. The most frequently mutated gene in hereditary breast cancers, BRCA1, is essential for homologous recombination (HR), a fundamental process for maintaining genome stability that permits the reactivation of blocked replication forks . Recent studies have established links between DDR and the oncogenic kinase AKT1, which is upregulated in about 50% of sporadic breast cancers. More specifically, the activation of AKT1 shows a deficient phenotype in BRCA1 and HR, revealing molecular similarities between hereditary and sporadic breast cancers. However, these results reveal a paradox regarding the physiological role of AKT1: in non-tumor cells, AKT1 promotes cellular proliferation, but consequently endangers genome integrity during replication if HR is inhibited. Since HR could itself lead to genetic instability, we propose that, under physiological conditions, moderate activation of AKT1 does not inhibit but prevents an excess of HR. The regulation of AKT1 would represent a fine transitory system for controlling HR and maintaining genomic integrity.The coordination of a complex network of metabolic pathways ensures continued maintenance, duplication, and transmission of the genome. These metabolic pathways control the DNA damage response pathway (DDR) and bring together replication, recombination, DNA repair, chromosome segregation, and cell cycle control. However, in some common tightly-regulated processes, such as meiosis and the generation of the immune repertory, this network must allow/favor genetic diversity. Therefore, very precise regulation is necessary to control the equilibrium between genetic stability and diversity, while avoiding genetic instability. A defect in any of the actors in these pathways could result in genetic instability and a predisposition to tumor formation.Certain types of cancers correspond to areas exposed to oncogenic agents (often genotoxic), such as UV radiation for skin cancer or tobacco for throat or lung cancer. However, we emphasize that many cancers develop without substantial exposure to exogenous carcinogens. Therefore, endogenous stresses must play crucial roles in the etiology of cancer. For example, mutating the BRCA1 or BRCA2 genes confers a hereditary predisposition to breast cancer in the absence of exposure to exogenous genotoxic agents. the replicAtion/recombinAtion interfAce, genetic instAbility, And cAncer.Among endogenous stresses, the spontaneous blocking of replication forks could constitute a risk for spontaneous tumor initiation. In fact, DNA replication forks are regularly blocked by a variety of endogenous stresses that can result from bulging regions in the DNA, regions of hybrid DNA/RNA, and from endogenous metabolism of the cell [1]. Furthermore, ...

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confidence: 53%

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confidence: 92%

AKT1/BRCA1 in the control of homologous recombination and genetic stability: the missing link between hereditary and sporadic breast cancers

2010

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“…Replication forks are routinely inactivated by endogenous stress (17,18); therefore, HR should play an essential role to protect cells against these types of stresses, and HR deficiency should reveal endogenous replication stress. Remarkably, unchallenged HR-deficient (HR − ) cells display both a genome-wide decrease in replication fork speed (19) and a spontaneous increase in the frequency of cells containing extra centrosomes (20)(21)(22)(23)(24)(25)(26)(27)(28). Two hypotheses may account for these two phenotypes.…”

mentioning

confidence: 99%

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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“…Some metabolic pathways can more or less directly repress HR. This is the • case in p53 (for a review, see Bertrand et al 2004 ) , in the activation of AKT1 (Plo et al 2008 ;Plo and Lopez 2009 ) or in expression of members of the Bc1-2 family (Laulier et al 2011a ) . Other cellular metabolic pathways affecting HR are likely to be discovered.…”

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confidence: 97%

“…Recently, several studies have shown connections between AKT1 and DNA damage response (for a review, see Guirouilh-Barbat et al 2010 ) . In particular, overexpression of AKT1 induces the sequestration of BRCA1 and RAD51 in the cytoplasm, leading to inhibition of HR (Plo et al 2008 ;Plo and Lopez 2009 ) . Taken together, these data underline the importance of HR in protection against breast cancer and reveal that the AKT1 signaling pathway is the missing link between hereditary and sporadic breast cancers.…”

Section: Deregulation Of Hr and Tumor Predispositionmentioning

confidence: 99%

Homologous Recombination in Mammals

Barascu

Grabarz

Lopez

2012

Site-Directed Insertion of Transgenes

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Homologous recombination (HR) is a fundamental process that is conserved in all species and is essential for maintaining genome stability while facilitating genetic diversity but avoiding genetic instability. As such, HR is involved in numerous fundamental biological processes, controlling a balance of genetic stability/diversity instability. This chapter summarizes the different models of recombination in mammals and then presents the following molecular steps of HR: recognition of damage, chromatin remodeling, DNA single-strand resection, strand invasion and resolution of Holliday junctions. HR is a process involved in DNA repair (notably double-strand breaks), the tolerance of damages and the reactivation of stalled replication forks; it is essential for the maintenance of genome stability. Conversely, an excess of HR (for example, between dispersed repeated sequences in the genome) can lead to genetic instability. In this context, the regulation of HR restricting it to S-phase is a factor in genetic stability. Deregulation of HR (causing a defect or an excess) is often found in tumor cells and tumor predisposition situations, illustrating the need for precise control of balance in HR. Knowledge of the molecular mechanisms of HR is also of interest in applications because it may provide strategies for the optimization of targeted in gene replacement.

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

Cited by 22 publications

References 31 publications

AKT1/BRCA1 in the control of homologous recombination and genetic stability: the missing link between hereditary and sporadic breast cancers

AKT1/BRCA1 in the control of homologous recombination and genetic stability: the missing link between hereditary and sporadic breast cancers

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

Homologous Recombination in Mammals

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