Role of BRCA2 in the response to replication inhibitors

BRCA2 在复制抑制剂反应中的作用

• 批准号: MR/J007595/1
• 负责人: Eva Petermann
• 金额: $ 44.56万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FJ007595%2F1
• 关键词: Role; BRCA2; response; replication; inhibitors

Some cancer patients have specific genetic defects in their cancer cells that influence their response to anti-cancer treatment. Patients with cancers such as breast and pancreatic cancer can have mutations in the BRCA2 gene, which makes their cancer cells less able to repair damage in their chromosomal DNA. This is important for therapy because many anti-cancer treatments work by causing deadly damage to the DNA. Patients with and without mutations in BRCA2 do therefore respond differently to some of these treatments. DNA-damaging drugs include agents called replication inhibitors such as Gemcitabine, which are used for chemotherapy of breast and pancreatic cancer. How cancer cells with BRCA2 mutations respond to replication inhibitors is not well understood. This project aims to characterise how BRCA2 prevents and repairs DNA damage in cells treated with replication inhibitors to generate new insights into the treatment response in genetic backgrounds frequently found in cancer patients.

一些癌症患者的癌细胞中存在特定的基因缺陷，这会影响他们对抗癌治疗的反应。患有乳腺癌和胰腺癌等癌症的患者可能存在BRCA2基因突变，这会使他们的癌细胞修复染色体DNA损伤的能力降低。这对治疗很重要，因为许多抗癌治疗都是通过对DNA造成致命损害来发挥作用的。因此，BRCA2基因突变和不突变的患者对其中一些治疗的反应不同。破坏DNA的药物包括被称为复制抑制剂的药物，如用于乳腺癌和胰腺癌化疗的吉西他滨。BRCA2突变的癌细胞对复制抑制剂的反应还不是很清楚。该项目旨在描述BRCA2如何预防和修复经复制抑制剂治疗的细胞中的DNA损伤，以对癌症患者经常发现的遗传背景下的治疗反应产生新的见解。

项目成果

BRCA2 and RAD51 promote double-strand break formation and cell death in response to gemcitabine.

• DOI: 10.1158/1535-7163.mct-13-0862
• 发表时间: 2014-10
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: Jones RM;Kotsantis P;Stewart GS;Groth P;Petermann E
• 通讯作者: Petermann E

Increased global transcription activity as a mechanism of replication stress in cancer.

• DOI: 10.1038/ncomms13087
• 发表时间: 2016-10-11
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Kotsantis, Panagiotis;Silva, Lara Marques;Irmscher, Sarah;Jones, Rebecca M.;Folkes, Lisa;Gromak, Natalia;Petermann, Eva
• 通讯作者: Petermann, Eva

Diminished origin-licensing capacity specifically sensitizes tumor cells to replication stress.

• DOI: 10.1158/1541-7786.mcr-12-0491
• 发表时间: 2013-04
• 期刊: Molecular cancer research : MCR
• 作者: Zimmerman KM;Jones RM;Petermann E;Jeggo PA
• 通讯作者: Jeggo PA