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Review
. 2010 Dec;1(8):691-699.
doi: 10.18632/oncotarget.203.

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

Josée Guirouilh-Barbat, Therese Wilhelm, Bernard S Lopez
Review

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

Josée Guirouilh-Barbat et al. Oncotarget. 2010 Dec.

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.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1:
Figure 1:. A Model for double-strand break repair by homologous recombination [78]
a) A DSB in the DNA generates regions of ssDNA. This step is promoted by the RAD50/MRE11/NBS1 complex associated with CtIP in mammals [79-82]. b) ssDNA is covered by the RPA (Replication protein A) protein. c) RAD52 (in yeast) or BRCA2 (in mammals) displaces RPA from the ssDNA and loads the key protein for HR, RAD51. d) The ssDNA-RAD51 complex finds the intact homologous double-stranded DNA and promotes the exchange of identical strands and the hybridization of complementary strands. e) DNA polymerase fills in the gap and moves the displacement loop (D-loop). f) The cruciform junctions (Holliday junctions) are then formed. g) The resolution of the Holliday junctions depends on the direction of resolution and can proceed via the following two mechanisms: without crossing over or with crossing over (exchange of adjacent DNA sequences).
Figure 2:
Figure 2:. Examples of the role of HR in restarting blocked replication forks [14-16]
a. A DSB can be generated by the collapse of a replication fork, for example due to a nick in the matrix. HR allows replication to restart by reinitiating it on the sister chromatid. b. When a fork reaches a blocking lesion, it can be reverted by generating a so-called “chickenfoot” structure. b-1. This structure has a DSB that can be used to initiate HR upstream of the blockage (given that the sequences are homologous). b-2. Alternatively, the cruciform structure can be resolved by specific endonucleases, which also generate DSBs. Replication can then be reactivated by HR using the sister chromatid.
Figure 3:
Figure 3:. Genetic instability linked to excess of homologous recombination
A. Chromosomal rearrangements resulting from crossing over (CO). 1. CO between repetitive sequences on two chromosomes or during an unequal sister chromatids exchange, resulting in an amplification on one molecule and a deletion on the other. 2. Intra-chromatid CO between two direct repeats, resulting in excision of the internal fragment. 3. Intra-chromatid CO between inversely oriented sequences, resulting in inversion of the internal fragment. 4. and 5. Inter-chromosomal CO. Depending on the orientation of the sequence with respect to the centromere (blue or red circles), the process will generate a translocation (4) or a dicentric chromosome and an acentric chromosome (5). B. Genetic modifications resulting from gene conversion without crossing over. Top: between two heteroalleles, leading to a loss of heterozygosity. Bottom: gene conversion between a pseudogene (hatch-marked), which often contains stop codons, and a gene, resulting in inactivation of the gene. Mutations are shown in red.
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