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pSer784-VCP: a clinically relevant link between autophagy and DNA damage response

pSer784-VCP：自噬和 DNA 损伤反应之间的临床相关联系

基本信息

批准号：
10435173
负责人：
Jieya Shao
金额：
$ 22.09万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10435173
关键词：
ATP phosphohydrolase Affect Antibodies Autophagocytosis Autophagosome Biogenesis Biological Breast Cancer Cell Breast Cancer Patient Breast Cancer cell line Bypass C-terminal Cancer Patient Cell Line Cell Nucleus Cell Survival Cells Chemoresistance Chemosensitization Chromatin Clinical Combined Modality Therapy Custom Cytoplasm DNA Damage DNA Repair Data Dependence Etiology Event Fluorescence Genetic Genome Stability Grant Homeostasis Human Cell Line Knowledge Link Lysosomes Malignant Neoplasms Mammary Neoplasms Mediating Methods Modeling Molecular Chaperones Mutagens Names Nuclear Nuclear Export Organelles Pathway interactions Pharmacology Phosphorylation Photobleaching Physiological Process Prognostic Marker Proteasome Inhibition Proteins Reporting Resistance Role SDZ RAD Sampling Serum Signal Transduction Sirolimus Stains Starvation Stress Tail Testing Therapeutic Ubiquitin Work cancer cell cancer therapy chemosensitizing agent chemotherapy chromatin protein clinically relevant experimental study genotoxicity improved inhibitor insight mTOR Inhibitor malignant breast neoplasm mimetics multicatalytic endopeptidase complex novel programs repaired response therapeutically effective triple-negative invasive breast carcinoma

项目摘要

PROJECT SUMMARY Autophagy and DNA damage response (DDR) are two evolutionarily conserved, fundamentally important cellular programs. Both can be deregulated in cancer and in turn targeted as cancer therapies. Despite compelling evidence that autophagy and DDR are connected, the scarce number of known DDR-relevant autophagy targets greatly limits our understanding of their functional crosstalk. Mixed reports regarding the chemotherapy-sensitizing effect of autophagy activation strongly suggest the context-dependency of the physiological role of autophagy in DDR. We hypothesize that this context-dependency could be determined by the functional importance of the affected autophagy targets for DDR. In this grant, we focus on an important DDR factor named VCP. VCP is a ubiquitously expressed AAA+ ATPase which recognizes polyubiquitinated proteins and facilitates their degradation by both the ubiquitin-proteasome and autophagy/lysosome pathways. Our recent work showed that DNA damage-induced Ser784 phosphorylation selectively increases nuclear VCP function for DDR. Importantly, pSer784-VCP is poor prognostic marker for chemotherapy-treated breast cancer patients. These data suggest that targeting pSer784-VCP may be a novel and effective chemo-sensitizing approach. In this grant, we present preliminary data showing that pSer784-VCP may be a previously unrecognized target of autophagy. In Aim 1, we will define the specific autophagy pathway that is involved in pSer784-VCP degradation and seek for direct evidence that pSer784-VCP undergoes nuclear export upon DNA damage. In Aim 2, we will test in a large panel of triple-negative breast cancer cell lines whether DNA damage-induced pSer784-VCP levels predict chemo-sensitizing effects of autophagy modulators. Together, these experiments will improve our understanding of the functional crosstalk between autophagy and DDR, and help define the biological context within which co-targeting of these two cellular programs can be therapeutically beneficial.

项目概要自噬和 DNA 损伤反应 (DDR) 是两个进化保守的、极其重要的蜂窝程序。两者都可以在癌症中解除管制，从而成为癌症治疗的目标。尽管令人信服的证据表明自噬和 DDR 是相关的，但已知的 DDR 相关的证据很少自噬靶标极大地限制了我们对其功能串扰的理解。关于该问题的报告不一自噬激活的化疗增敏作用强烈表明自噬的环境依赖性自噬在 DDR 中的生理作用。我们假设这种上下文依赖性可以通过以下方式确定受影响的自噬靶点对 DDR 的功能重要性。在这笔赠款中，我们重点关注一个重要的 DDR因子命名为VCP。 VCP 是一种普遍表达的 AAA+ ATP 酶，可识别多聚泛素化蛋白质并通过泛素蛋白酶体和自噬/溶酶体途径促进其降解。我们最近的工作表明 DNA 损伤诱导的 Ser784 磷酸化选择性地增加核 VCP DDR 功能。重要的是，pSer784-VCP 是化疗治疗乳腺癌的不良预后标志物患者。这些数据表明，靶向 pSer784-VCP 可能是一种新颖且有效的化疗增敏剂。方法。在这笔资助中，我们提供了初步数据，表明 pSer784-VCP 可能是以前的未被识别的自噬靶点。在目标 1 中，我们将定义参与的特定自噬途径 pSer784-VCP 降解并寻求 pSer784-VCP 经历核输出的直接证据 DNA损伤。在目标 2 中，我们将在一大组三阴性乳腺癌细胞系中测试 DNA 是否损伤诱导的 pSer784-VCP 水平可预测自噬调节剂的化疗增敏作用。一起，这些实验将提高我们对自噬和 DDR 之间功能串扰的理解，并帮助定义可以共同靶向这两个细胞程序的生物学背景有治疗效果。