Role of BRCA1 phosphorylation in DNA DSB repair and genome stability maintenance

肿瘤抑制因子BRCA 1在同源重组（HR）途径中起重要作用 DNA双链断裂（DSB）修复。从机制的角度来看，BRCA 1有助于招募 BRCA 1是末端切除所需的核酸酶，是HR修复中的承诺步骤，但矛盾的是，BRCA 1一直是 显示在体外抑制核酸酶活性。目前还不清楚， BRCA 1可在HR修复中协调。从癌症病理生理学的角度来看，大多数BRCA 1- 相关的乳腺肿瘤是基底样的，但它们起源于管腔祖细胞，即所谓的起源细胞。 这提出了一个重要的和很大程度上未解决的问题：BRCA 1是否影响HR修复和基因组 细胞谱系和基因座偏好方式的稳定性？ 我们的初步数据表明，BRCA 1的修饰标志着它及时离开DSB， 有效地中和其对DSB核酸酶抑制活性。使用临床样本，我们还发现鲁米那 来自BRCA 1突变携带者的细胞对放射特别敏感，并且易于DSB积累 在特定的基因组位点的前体。基于这些令人信服的初步数据，我们假设BRCA 1 修改是将HR的承诺步骤限制在S/G2阶段的许可机制的一部分。我们 进一步提出，BRCA 1 HR修复活性对管腔基因的遗传完整性特别重要， 乳腺组织的腔细胞。我们的实验室和临床医生科学家多学科团队将联合收割机 细胞培养系统与小鼠遗传学和人类样本，以测试这一新的假设。 我们提出的工作旨在验证BRCA 1在许可中的一个先前未被认识的作用， 因此，BRCA 1仅仅是一种支架蛋白的观点受到了挑战。 此外，通过在临床相关细胞谱系和基因组区域中询问BRCA 1 HR功能， 我们的工作代表了与传统的以细胞系为中心的机制研究的显著不同。我们提出的 这项工作有助于填补BRCA 1机制研究与组织/细胞病因学之间的关键知识空白 谱系特异性BRCA 1相关肿瘤的发展，从而显著促进BRCA 1相关乳腺癌的发生。 癌症研究。

The tumor suppressor BRCA1 plays an important role in the homologous recombination (HR) pathway of DNA double strand break (DSB) repair. From a mechanistic perspective, BRCA1 facilitates recruitment of nucleases required for end resection, the commitment step in HR repair, yet paradoxically, BRCA1 has been shown to inhibit the nuclease activity in vitro. It is unclear how nuclease-recruiting and -inhibiting activities of BRCA1 can be reconciled in HR repair. From a cancer pathophysiological perspective, most BRCA1- associated breast tumors are basal-like but they originate from luminal progenitor cells, so-called cells of origin. This poses an important and largely unaddressed question: does BRCA1 influence HR repair and genome stability in a cell lineage- and genomic locus-preferred manner? Our preliminary data indicate that BRCA1 modifications signal its timely departure from DSBs and thus effectively neutralize its nuclease-inhibiting activity at DSB. Using clinical samples, we also found that luminal cells from BRCA1 mutation carriers are particularly radiosensitive and prone to accumulation of DSB precursors at specific genomic loci. Based on these compelling preliminary data, we hypothesize that BRCA1 modifications are part of a licensing mechanism that confines the commitment step of HR to S/G2 phase. We further propose that BRCA1 HR repair activity is particularly important for genetic integrity at luminal genes in luminal cells of the breast tissue. Our multidisciplinary team of laboratory and clinician scientists will combine cell culture systems with mouse genetics and human samples to test this novel hypothesis. Our proposed work seeks to validate a previously unrecognized role of BRCA1 in licensing the commitment step in HR, thus challenging the current view of BRCA1 merely as a scaffolding protein. Furthermore, by interrogating BRCA1 HR function in the clinically relevant cell lineage and genomic regions, our work represents a significant departure from traditional cell line-focused mechanistic studies. Our proposed work helps fill a critical knowledge gap between mechanistic investigation of BRCA1 and etiology of tissue/cell lineage-specific BRCA1-associated tumor development, thus substantially advancing BRCA1-related breast cancer research.