Functional characterisation of a novel BRCA1-mRNA splicing complex that is mutated in multiple cancers.

出生时携带BRCA1基因遗传突变的女性一生中患乳腺癌和卵巢癌的风险非常高。这些女性往往有很强的乳腺癌家族史，并可能在年轻时患上乳腺癌。此外，很大一部分零星发展的乳腺癌(非遗传性乳腺癌)已经失去了BRCA1基因的功能。BRCA1在细胞中的主要作用是修复和维持DNA，通过这样做，BRCA1保护细胞不会转化为癌症。然而，BRCA1保护和修复受损DNA的确切机制仍不清楚。然而，最近在如何治疗BRCA1相关癌症方面取得了重大进展，出现了名为PARP抑制剂的“靶向”癌症疗法，这种疗法可以特异性地杀死像BRCA1相关的癌症，这些癌症在修复受损DNA的能力上存在缺陷。我们最近发现了BRCA1的一种新功能，它在其他称为mRNA剪接蛋白的蛋白质的帮助下，通过调节细胞内DNA修复蛋白的水平，并确保有足够的这些蛋白质来修复受损的DNA，来帮助细胞修复受损的DNA。最近，在相当大比例的乳腺癌、卵巢癌和血液癌中也发现了帮助BRCA1实现这一新功能的mRNA剪接蛋白的一些突变。这项研究的目的是：1)确定BRCA1的遗传突变是否以及如何影响BRCA1的这一新功能，帮助我们了解BRCA1的这一新功能是否真的在遗传性癌症的发生发展中发挥作用。2)确定BRCA1和其他mRNA剪接蛋白调控的哪些DNA修复蛋白对BRCA1执行其DNA修复功能非常重要。3)了解帮助BRCA1修复受损DNA的mRNA剪接蛋白中与癌症相关的突变如何影响这些蛋白质帮助BRCA1修复受损DNA的方式，以及它们如何影响癌症对不同治疗的反应。这项拟议的研究将大大加深我们对BRCA1如何作用于预防癌症发展的理解。此外，这项研究可能会导致开发新的测试，以帮助确定特定癌症患者将从哪些治疗中受益，并可能识别与癌症相关的新蛋白质，这些蛋白质可能是未来治疗的目标。

Women who are born with an inherited mutation in the BRCA1 gene have a very high lifetime risk of developing breast and ovarian cancer. These women tend to have a strong family history of breast cancer and can develop breast cancer at a young age. Additionally, a large proportion of breast cancer that develop sporadically (non-inherited breast cancers) have lost the function of the BRCA1 gene. BRCA1s primary role in cells is to repair and maintain DNA and by doing this BRCA1 protects cells from being able to turn into cancers. However, the exact mechanisms through which BRCA1 protects and repairs damaged DNA remain unknown. Nevertheless, recently there have been significant advances in how BRCA1 related cancers are treated with the advent of "targeted" cancer therapies called PARP inhibitors that specifically kill cancers like BRCA1 linked cancers that have defects in their ability to repair damaged DNA. We have recently identified a new function for BRCA1 where it, with the help of other proteins called mRNA splicing proteins, helps cells to repair damaged DNA by regulating the levels of DNA repair proteins within a cell and ensuring there is enough of these proteins to repair DNA that has been damaged. Recently, a number of mutations have also been found in a significant proportion of breast, ovarian and haematological cancers in the mRNA splicing proteins that help BRCA1 carry out this new function. The proposed research in this project aims to: 1) Identify if and how hereditary mutations in BRCA1 affect this new function of BRCA1 helping us to understand whether this new function of BRCA1 really plays a role in the development of hereditary cancers. 2) Identify which DNA repair proteins that BRCA1 and the other mRNA splicing proteins, regulate are important for BRCA1 to carry out it's DNA repair functions.3) Understand how cancer associated mutations in the mRNA splicing proteins that help BRCA1 repair damaged DNA affect the way these proteins are able to help BRCA1 repair damaged DNA and how they affect the way that cancers respond to different treatments. The proposed research will add significantly to our understanding of how BRCA1 works to prevent the development of cancer. Additionally, this research may lead to the development of new tests to help decide which treatments specific cancer patients will benefit from and may also identify new proteins associated with cancer that could be targeted for future therapies.