Role of PALB2 in the DNA Damage Response and Cancer Suppression

 描述（由申请人提供）：PALB 2是一种肿瘤抑制蛋白，在物理和功能上连接两种主要的乳腺癌抑制因子BRCA 1和BRCA 2。这3种蛋白形成“BRCA”复合物，并在DNA损伤后的DNA双链断裂（DSB）修复和细胞周期检查点控制中共同起作用。这些功能对于维持基因组稳定性和抑制肿瘤发生至关重要。我们和其他人已经证明BRCA 1在PALB 2和BRCA 2的上游发挥作用。然而，BRCA 1如何在各种DSB修复途径中调节PALB 2仍然知之甚少，并且这3种蛋白如何促进检查点反应的机制仍然未知。此外，BRCA 1的肿瘤抑制功能有多少是由PALB 2传递的，以及PALB 2的体内功能在多大程度上依赖于BRCA 1也是未知的。在这个项目中，我们将深入研究BRCA 1-PALB 2-BRCA 2 DNA损伤反应网络的分子基础，以了解管理DSB修复效率，途径选择和检查点控制的关键调控机制。此外，我们还将使用我们新产生的Palb 2敲入小鼠，其中内源性PALB 2不能结合BRCA 1，以探索PALB 2和BRCA 1相关癌症的病因学和组织特异性。在Aim 1中，我们将研究BRCA 1-PALB 2相互作用在同源重组（HR）和单链退火（SSA）中的作用和机制。在目标2中，我们将定义BRCA 1，PALB 2和BRCA 2在G2/M检查点控制中的机制。在Aim 3中，我们将使用上述小鼠模型来探索BRCA 1-PALB 2复合物形成在体内DNA损伤反应和不同组织中肿瘤抑制中的作用。

 DESCRIPTION (provided by applicant): PALB2 is tumor suppressor protein that physically and functionally links BRCA1 and BRCA2, the two major breast cancer suppressors. The 3 proteins form a "BRCA" complex and function together in DNA double strand break (DSB) repair and cell cycle checkpoint control following DNA damage. These functions are critical for the maintenance of genome stability and suppressing tumorigenesis. We and others have shown that BRCA1 functions upstream of PALB2 and BRCA2. However, how BRCA1 regulates PALB2 in various DSB repair pathways remain poorly understood, and the mechanism how the 3 proteins promote checkpoint response remains unknown. Moreover, how much of BRCA1's tumor suppressive function is transmitted by PALB2 and to what extent PALB2's in vivo function depends on BRCA1 are also unknown. In this project, we will delve into the molecular underpinnings of the BRCA1- PALB2-BRCA2 DNA damage response network to understand key regulatory mechanisms that govern DSB repair efficiency, pathway choice and checkpoint control. Moreover, we will also use our newly generated Palb2 knockin mouse, in which the endogenous PALB2 is unable to bind BRCA1, to explore the etiology and tissue specificity of PALB2- and BRCA1-associated cancers. In Aim1, we will investigate the role and mechanism of the BRCA1-PALB2 interaction in homologous recombination (HR) and single strand annealing (SSA). In Aim2, we will define the mechanism of BRCA1, PALB2 and BRCA2 in the G2/M checkpoint control. In Aim3, we will use the above mouse model to explore the role of the BRCA1-PALB2 complex formation in the DNA damage response in vivo and in tumor suppression in different tissues.