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The RAD51-FFPE Test; Calibration of a Functional Homologous Recombination Deficiency Test on Diagnostic Endometrial and Ovarian Tumor Blocks

BRCA2 Promotes Spontaneous Homologous Recombination In Vivo

Department of Cellular Systems and Anatomy, University of Texas Health San Antonio, San Antonio, TX 78229, USA
Greehey Children’s Cancer Research Institute, University of Texas Health San Antonio, San Antonio, TX 78229, USA
Department of Exercise Sciences, Brigham Young University, Provo, UT 84602, USA
Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX 78229, USA
Author to whom correspondence should be addressed.
Academic Editors: Jos Jonkers and Amit Manulal Oza
Cancers 2021, 13(15), 3663;
Received: 28 May 2021 / Revised: 12 July 2021 / Accepted: 15 July 2021 / Published: 21 July 2021
(This article belongs to the Special Issue Homolog Recombination Deficiency, Genetics in Ovarian Cancer)
Inherited mutation of either BRCA1 or BRCA2 is associated with familial breast and ovarian cancer. As a tumor suppressor, BRCA2 functions to maintain genome stability but we do not know the genomic impact of this deficiency on normal tissues in normal contexts, rather than cancer cells that carry other gene mutations. Numerous murine models of BRCA2 have been developed to investigate BRCA2 tumor suppressor function but have been met with difficulties due to the lethality of most of these models during embryogenesis. To circumvent embryonic lethality here, we employ the cre conditional system combined with an assay for measuring changes in stability of a large tandem DNA repeat by homology-directed recombination. The relevance of this assay is that it can measure DNA recombination events in a normal growing/developing tissue. Here, we show that BRCA2 is required for homologous recombination in a normal developing tissue long before cancer arises.
Background: BRCA2 is known to be a tumor suppressor involved in homologous recombination repair and presumed to prevent genome instability in normal tissues prior to the development of tumors. Typical assessment of BRCA2 deficiency on the genome involves cell-based models using cancer cells with mixed genetic contexts, but the role in normal tissue in vivo has not been clearly demonstrated. Methods: Using conditional deletion of Brca2 exon 11, the region containing all eight BRC repeats, in the retinal pigment epithelium and the pink-eyed unstable mouse model, we evaluate the frequency of DNA deletion events. Results: In the current study, we show that conditional loss of Brca2 exon 11 results in a decreased frequency of spontaneous homologous recombination compared to wild-type mice. Of note, we observe no apparent concomitant increase in events that indicate single-strand annealing by the pink-eyed unstable mouse model. Conclusions: Therefore, our results demonstrate that BRCA2, as expected, is required for high-fidelity homologous recombination DNA repair in normal tissues, here in a tissue undergoing normal proliferation through normal development. View Full-Text
Keywords: BRCA2; homologous recombination; pink-eyed unstable; mouse BRCA2; homologous recombination; pink-eyed unstable; mouse
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MDPI and ACS Style

Brown, A.D.; Greenman, S.; Claybon, A.B.; Bishop, A.J.R. BRCA2 Promotes Spontaneous Homologous Recombination In Vivo. Cancers 2021, 13, 3663.

AMA Style

Brown AD, Greenman S, Claybon AB, Bishop AJR. BRCA2 Promotes Spontaneous Homologous Recombination In Vivo. Cancers. 2021; 13(15):3663.

Chicago/Turabian Style

Brown, Adam D., Scott Greenman, Alison B. Claybon, and Alexander J.R. Bishop. 2021. "BRCA2 Promotes Spontaneous Homologous Recombination In Vivo" Cancers 13, no. 15: 3663.

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