Brown Adam D, Greenman Scott, Claybon Alison B, Bishop Alexander J R
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.
Cancers (Basel). 2021 Jul 21;13(15):3663. doi: 10.3390/cancers13153663.
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.
Using conditional deletion of 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.
In the current study, we show that conditional loss of 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.
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.
已知BRCA2是一种参与同源重组修复的肿瘤抑制因子，推测其在肿瘤发生前可防止正常组织中的基因组不稳定。对基因组中BRCA2缺陷的典型评估涉及使用具有混合遗传背景的癌细胞的基于细胞的模型，但BRCA2在体内正常组织中的作用尚未得到明确证实。
利用视网膜色素上皮细胞中外显子11（包含所有八个BRC重复序列的区域）的条件性缺失以及粉红眼不稳定小鼠模型，我们评估了DNA缺失事件的频率。
在本研究中，我们发现与野生型小鼠相比，外显子11的条件性缺失导致自发同源重组频率降低。值得注意的是，我们未观察到粉红眼不稳定小鼠模型中表明单链退火的事件有明显的伴随增加。
因此，我们的结果表明，正如预期的那样，BRCA2是正常组织中高保真同源重组DNA修复所必需的，此处是指在通过正常发育进行正常增殖的组织中。
