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

在多种癌症中发生突变的新型 BRCA1-mRNA 剪接复合物的功能表征。

• 批准号: MR/K018965/1
• 负责人: Dennis Harkin
• 金额: $ 84.5万
• 依托单位: Queen's University Belfast
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK018965%2F1
• 关键词: Functional; characterisation; novel; BRCA1; mRNA

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.

出生时携带BRCA1基因遗传突变的女性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，可能在年轻时患上乳腺癌。此外，很大一部分偶发的乳腺癌（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保护细胞不变成癌症。然而，BRCA1保护和修复受损DNA的确切机制尚不清楚。然而，最近在如何治疗BRCA1相关癌症方面取得了重大进展，因为一种名为PARP抑制剂的“靶向”癌症疗法的出现，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mRNA剪接蛋白的帮助下，通过调节细胞内DNA修复蛋白的水平，帮助细胞修复受损的DNA，并确保有足够的这些蛋白质来修复受损的DNA。最近，在很大比例的乳腺癌、卵巢癌和血液学癌症中，也发现了一些帮助BRCA1执行这种新功能的mRNA剪接蛋白的突变。本项目拟开展的研究旨在：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发挥其DNA修复功能是重要的。3)了解帮助BRCA1修复受损DNA的mRNA剪接蛋白中的癌症相关突变如何影响这些蛋白质能够帮助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方式。拟议的研究将大大增加我们对BRCA1如何预防癌症发展的理解。此外，这项研究可能会导致新的测试的发展，以帮助确定哪些治疗方法对特定的癌症患者有益，也可能确定与癌症相关的新蛋白质，这些蛋白质可能成为未来治疗的目标。

项目成果

BRCA1 deficiency exacerbates estrogen-induced DNA damage and genomic instability.

• DOI: 10.1158/0008-5472.can-13-2611
• 发表时间: 2014-05-15
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Savage KI;Matchett KB;Barros EM;Cooper KM;Irwin GW;Gorski JJ;Orr KS;Vohhodina J;Kavanagh JN;Madden AF;Powell A;Manti L;McDade SS;Park BH;Prise KM;McIntosh SA;Salto-Tellez M;Richard DJ;Elliott CT;Harkin DP
• 通讯作者: Harkin DP

Cancer-Associated SF3B1 Mutations Confer a BRCA-Like Cellular Phenotype and Synthetic Lethality to PARP Inhibitors.

• DOI: 10.1158/0008-5472.can-21-1843
• 发表时间: 2022-03-01
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Lappin KM;Barros EM;Jhujh SS;Irwin GW;McMillan H;Liberante FG;Latimer C;La Bonte MJ;Mills KI;Harkin DP;Stewart GS;Savage KI
• 通讯作者: Savage KI

Cryptic splicing events in the iron transporter ABCB7 and other key target genes in SF3B1-mutant myelodysplastic syndromes.

• DOI: 10.1038/leu.2016.149
• 发表时间: 2016-12
• 期刊: Leukemia
• 影响因子: 11.4

Activation of STING-Dependent Innate Immune Signaling By S-Phase-Specific DNA Damage in Breast Cancer.

• DOI: 10.1093/jnci/djw199
• 发表时间: 2017-01
• 期刊: Journal of the National Cancer Institute
• 作者: Parkes EE;Walker SM;Taggart LE;McCabe N;Knight LA;Wilkinson R;McCloskey KD;Buckley NE;Savage KI;Salto-Tellez M;McQuaid S;Harte MT;Mullan PB;Harkin DP;Kennedy RD
• 通讯作者: Kennedy RD