Homology-directed repair: BRCA2 and RAD51 paralogs

同源定向修复：BRCA2 和 RAD51 旁系同源物

• 批准号: 10697318
• 负责人: Maria Jasin
• 金额: $ 99.94万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10697318
• 关键词: Address; Affect; Alleles; Area; BRCA2 gene; Breast; Cell Death; Cells; Cisplatin; Constitution; Constitutional; DNA Damage; DNA Repair; DNA Sequence Rearrangement; DNA biosynthesis; Defect; Epithelium; Frequencies; Genes; Genome; Genome Stability; Genomic Instability; Germ-Line Mutation; Goals; Heterozygote; Homeostasis; Homologous Protein; Individual; Lesion; Loss of Heterozygosity; Malignant neoplasm of ovary; Mammalian Oviducts; Molecular Analysis; Mutation; Ovary; Pathway interactions; Poly(ADP-ribose) Polymerase Inhibitor; Predisposition; Proteins; Research; Resistance; Serous; Tissues; Tumor Suppressor Proteins; cancer therapy; chromosome loss; crosslink; homologous recombination; interest; malignant breast neoplasm; mutant; paralogous gene; protein function; repair function; repaired; targeted treatment; therapy resistant; treatment response; tumor; tumor initiation

Project Summary/Abstract Homologous recombination, i.e., homology-directed repair (HDR), is a major repair pathway for double-strand breaks (DSBs), including lesions arising during DNA replication. HDR mutants are characterized by genomic instability and sensitivity to DNA damaging agents such as interstrand cross-linking agents like cisplatin and poly(ADP-ribose) polymerase inhibitors, both of which are used in cancer treatment. Several proteins central to the HDR pathway are tumor suppressors, notably the breast and ovarian cancer suppressor BRCA2, which promotes the function of RAD51, the critical protein for homologous strand exchange. RAD51 paralogs are also key HDR proteins and have also been identified both as tumor suppressors and as proteins that affect therapy response. These HDR proteins are essential. Individuals with germline mutations are constitutionally heterozygous, but tumors typically have somatic undergone loss of heterozygosity (LOH), losing the wild-type allele, presumably as an early step in tumor initiation. This proposal has an overarching goal of integrating our understanding how HDR proteins act to maintain genomic stability and cell and tissue homeostasis, how they come to be “lost” in cells, and how their function can be restored. Thus, this broad goal impacts tumor initiation, therapy response, and therapy resistance. It incorporates molecular analysis of HDR protein function, with a particular focus on BRCA2, and delineates how cells respond to HDR protein loss, including how they escape cell death to allow tumor formation. Within this goal is understanding tumor initiation from the standpoint of determining mechanisms of LOH that lead to HDR protein loss, as well as uncovering factors that affect LOH frequencies. While HDR protein loss sensitizes tumors to targeted therapies, HDR function is often restored by secondary mutations, leading to therapy resistance. Understanding which mutations are susceptible to reversion and how therapy impacts reversion is of major interest. Finally, HDR within tissues is also part of this integrated goal, in particular, within the fallopian tube epithelium, which is considered the tissue of origin of high-grade serous ovarian cancers.

项目摘要/摘要 同源重组，即同源指导的维修（HDR），是双链的主要维修途径 断裂（DSB），包括在DNA复制过程中产生的病变。 HDR突变体的特征是基因组 不稳定性和对DNA破坏剂的敏感性，例如链间交联剂，如顺铂和 聚（ADP-核糖）聚合酶抑制剂，两者均用于癌症治疗。几种中心的蛋白质 HDR途径是肿瘤补充剂，特别是乳腺癌和卵巢癌抑制剂BRCA2，它 促进Rad51的功能，Rad51是同源链交换的关键蛋白质。 Rad51旁系同源物 还有关键的HDR蛋白质，也被确定为肿瘤补充剂和影响的蛋白质 治疗反应。这些HDR蛋白是必不可少的。种系突变的个体始终如一 杂合子，但肿瘤通常会造成杂合性的损失（LOH），失去了野生型 等位基因，大概是肿瘤开始的早期一步。 该提案的总体目标是将我们的理解HDR蛋白质的作用整合到 保持基因组稳定性，细胞和组织稳态，如何在细胞中“丢失”以及如何 功能可以恢复。这是这个广泛的目标影响肿瘤倡议，治疗反应和治疗 反抗。它结合了HDR蛋白功能的分子分析，特别关注BRCA2，并且 描述细胞对HDR蛋白损失的反应方式，包括它们如何逃脱细胞死亡以允许肿瘤 形成。在这个目标中，是从确定机制的角度理解肿瘤倡议 导致HDR蛋白丢失的LOH，以及影响LOH频率的因素。 hdr 蛋白质丧失感知到靶向疗法的肿瘤，HDR功能通常通过次级突变恢复， 导致耐药性。了解哪些突变容易逆转以及如何治疗 影响逆转是引起重大兴趣的。最后，组织内的HDR也是这个综合目标的一部分 特别是，在输卵管上皮中，这被认为是高级血清起源的组织 卵巢癌。

项目成果

Generating in vitro models of NTRK-fusion mesenchymal neoplasia as tools for investigating kinase oncogenic activation and response to targeted therapy.

• DOI: 10.1038/s41389-023-00454-6
• 发表时间: 2023-02-17
• 期刊: ONCOGENESIS
• 影响因子: 6.2
• 作者: Vanoli, Fabio;Herviou, Laurie;Tsuda, Yusuke;Sung, Patricia;Xie, Ziyu;Fishinevich, Eve;Min, Soe S.;Mallen, William;de Wardin, Henry de Traux;Zhang, Yanming;Jasin, Maria;Antonescu, Cristina R.
• 通讯作者: Antonescu, Cristina R.

Testicular Germ Cell Tumors Acquire Cisplatin Resistance by Rebalancing the Usage of DNA Repair Pathways.

• DOI: 10.3390/cancers13040787
• 发表时间: 2021-02-13
• 期刊: Cancers
• 影响因子: 5.2
• 作者: Caggiano C;Cavallo F;Giannattasio T;Cappelletti G;Rossi P;Grimaldi P;Feldman DR;Jasin M;Barchi M
• 通讯作者: Barchi M

Unraveling Ewing Sarcoma Tumorigenesis Originating from Patient-Derived Mesenchymal Stem Cells.

• DOI: 10.1158/0008-5472.can-20-3837
• 发表时间: 2021-10-01
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Sole A;Grossetête S;Heintzé M;Babin L;Zaïdi S;Revy P;Renouf B;De Cian A;Giovannangeli C;Pierre-Eugène C;Janoueix-Lerosey I;Couronné L;Kaltenbach S;Tomishima M;Jasin M;Grünewald TGP;Delattre O;Surdez D;Brunet E
• 通讯作者: Brunet E

XRCC3 loss leads to midgestational embryonic lethality in mice.

• DOI: 10.1016/j.dnarep.2021.103227
• 发表时间: 2021-12
• 期刊: DNA repair
• 影响因子: 3.8
• 作者: Prakash R;Freyer L;Saiz N;Gavrilov S;Wang RQ;Romanienko PJ;Lacy E;Hadjantonakis AK;Jasin M
• 通讯作者: Jasin M