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Stalled replication fork repair in cancer predisposition and cancertherapy

癌症易感性和癌症治疗中停滞的复制叉修复

基本信息

批准号：
10517824
负责人：
Ralph Scully
金额：
$ 102.2万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
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：
2022-08-10 至 2029-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10517824
关键词：
ATP phosphohydrolase Ablation BRCA1 gene BRCA2 gene Breast Cancer therapy Cell Cycle Cells Chromatin Clinical Code DNA DNA Damage DNA Repair DNA analysis DNA biosynthesis DNA replication fork Defect Disease Fanconi&apos s Anemia Funding Genes Genetic Genomic Instability Goals Hereditary Breast and Ovarian Cancer Syndrome Human Light Link Malignant Neoplasms Malignant neoplasm of ovary Motor Mutation Oncogenes Outcome Prevention Proteins Regulation Replication-Associated Process Reporter Rest Role Site Techniques Therapeutic Time Variant Work Yeasts cancer genome cancer predisposition druggable target homologous recombination human disease innovation insight loss of function mutation malignant breast neoplasm molecular targeted therapies mutant novel therapeutics prevent repaired response success targeted cancer therapy targeted treatment tool

项目摘要

PROJECT SUMMARY Error-free DNA repair initiated at the sites of replication fork stalling is critical for the prevention of genomic instability in cycling cells. Defects in stalled fork repair have been directly implicated in cancer predisposition and other human diseases. The clinical burden associated with failed stalled fork repair may include hereditary breast and ovarian cancer (HBOC) predisposition, in light of the involvement of BRCA1 and BRCA2 in repair of stalled replication forks, and Fanconi Anemia (FA)—a rare, autosomal recessive (or X-linked) disease caused by inactivation of any one of several FA genes. Our work previously established roles for BRCA1 and BRCA2 in regulating HR at both double strand breaks (DSBs) and in stalled fork repair. We developed innovative tools for quantifying homologous recombination (HR) and other repair outcomes at stalled mammalian replication forks and, more recently, at broken replication forks. A major goal of this proposal is to define the fundamental mechanisms of repair of stalled forks. We have developed an array of cutting-edge tools to support this study, including unique, sophisticated HR reporters that can distinguish between error-free “short tract” HR and error- prone “long tract” HR—a replicative response analogous to break-induced replication in yeast. One unusual aberrant replicative response that we observe at stalled forks specifically in BRCA1 mutant cells is the formation of <10 kb non-homologous tandem duplications (TDs). In a paradigm-shifting discovery, we found that these highly specific forms of structural variation are also abundant in the human BRCA1-linked breast and ovarian cancer genome. A major goal of this proposal is to define the genetic regulation and full mechanism of TD formation at stalled forks in BRCA1 mutant cells. Success in this project will reveal in unprecedented detail the mechanisms that regulate mammalian stalled (or broken) fork repair and their relationship to cancer predisposition. In support of this, we will develop new techniques for analyzing DNA structural intermediates, chromatin responses to fork stalling and protein composition of the stalled mammalian replication fork. These analytical studies may also identify new molecular targets for therapy of breast and ovarian cancer. Indeed, our recent work on the mechanisms underlying formation of BRCA1-linked TDs led us to discover a synthetic lethal interaction between BRCA1 and FANCM loss-of-function mutations. FANCM is a motor protein and, hence, an ATPase. We find that ablation of FANCM ATPase activity alone (leaving the rest of the protein intact and stable within the cell) is sufficient to confer lethality on BRCA1 mutant cells. Thus, FANCM may be a “druggable” target for therapy in BRCA1-linked cancer. In work proposed herein, we will define the therapeutic potential of this discovery. During the funding period, we expect to make important discoveries in this field and to open the door to new therapies in HBOC and perhaps other forms of cancer.

项目总结