Defining BRCA replication dysfunction in therapy response

这笔赠款的目标是利用对肿瘤易感性的新理解，这些肿瘤的基因突变 遗传性乳腺癌基因。我们已经发现，缺乏BRCA途径基因的细胞，不能正确地 对DNA复制扰动(应激)作出反应，因此复制没有得到适当的抑制 单链DNA区域(缺口)形成。我们发现，当存在缺口时，BRCA癌细胞对治疗敏感 当差距被避免时，就会产生阻力。我们的研究发现，差距是治疗反应的根本 当前框架中提出持续DNA断裂和分叉降解的范式转变是 因为敏感。因此，我们建议使用最先进的实验来绘制分子决定因素图 这种BRCA通路的分叉抑制功能。此外，将确定对以下方面至关重要的缝隙形成机制 治疗反应和缺口避免机制，这是治疗抵抗的关键。最后，我们将重新- 检查以前归因于恢复的DNA修复和分叉保护和 确定间隙抑制是否为基本阻力机制。总的来说，这些建议 研究将确定癌细胞如何屈服于化疗并最终获得抗药性，并提供 对预测耐药性的生物标记物和预防耐药性的药物的有价值的见解。

The goal of this grant is to harness a new understanding of vulnerabilities in tumors with mutations in the hereditary breast cancer genes. We have found that cells deficient in the BRCA-pathway genes, fail to properly respond to DNA replication perturbations (stress) and consequently replication is not restrained properly and ssDNA regions (gaps) develop. We find that when gaps are present, BRCA cancer cells are sensitive to therapy and when gaps are avoided, resistance occurs. Our findings that gaps are fundamental to therapy response is a paradigm shift in the current framework that proposes that persistent DNA breaks and fork degradation is the cause of sensitivity. Thus, we propose to employ state-of-the-art experiments to map the molecular determinants of this BRCA pathway fork restraint function. Moreover, will identify the gap making machinery that is critical for therapy response and the gap avoidance machinery that is critical to therapy resistance. Lastly, we will re- examine models of therapy resistance previously attributed to restored DNA repair and fork protection and determine if gap suppression is instead the fundamental resistance mechanism. Collectively, these proposed studies will identify how cancer cells succumb to and eventually gain resistance to chemotherapy and provide valuable insight towards biomarkers predicting resistance and drugs that prevent resistance.