权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

FANCD2 Monoubiquitination in DNA Damage Responses

DNA 损伤反应中的 FANCD2 单泛素化

基本信息

批准号：
8296565
负责人：
PAUL R ANDREASSEN
金额：
$ 33.41万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-08 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8296565
关键词：
Acute Myelocytic Leukemia Address Apoptosis CD34 gene Cell physiology Cells Chromosomal Instability Chromosome abnormality Complex Coupled Crosslinker DNA DNA Damage DNA Repair DNA biosynthesis Defect Detection Disease Dysmyelopoietic Syndromes Fanconi anemia protein Fanconi&apos s Anemia General Population Genes Goals Hematopoiesis Hematopoietic Human Hypersensitivity Lead Light Link MCM7 gene Malignant Neoplasms Mediating Microscopy Mitomycins Molecular Monoubiquitination Mus Mutate Myelogenous Normal Cell Nuclear Pancytopenia Pathogenesis Pathway interactions Patients Phenotype Phosphotransferases Predisposition Prevalence Proteins Recruitment Activity Regulation Resistance Role Site Stem cells Stress Study Section System Time abstracting base clinical phenotype insight leukemia mutant prevent progenitor protein function reconstitution response sensor small hairpin RNA stem

项目摘要

Abstract Fanconi Anemia (FA) is a multi-genic disorder that results in progressive bone marrow failure and a strong predisposition to myelodysplastic syndrome and leukemia. FA proteins are involved in the cellular response to DNA damage by a largely unknown mechanism. A nuclear complex of at least 8 FA proteins is required for the monoubiquitination of FANCD2. Monoubiquitination of FANCD2 is required for resistance to the crosslinker mitomycin C. The ATR checkpoint kinase also regulates FANCD2 monoubiquitination and potentially links FANCD2 to the detection of DNA damage at the replication fork. The goal of this study is to understand the regulation and function of FANCD2 monoubiquitination, and thereby to better understand the collective role of FA proteins in promoting normal hematopoiesis. Certain FA proteins are mutated in spontaneous cancers in the general population, so these studies are also relevant to understanding how cancer develops. The specific aims of the study are as follows: 1) Delineate mechanisms of the ATR-dependent regulation of FANCD2 monoubiquitination. How, and whether, MCM7 and Rad17, along with Rad9, cooperate to couple FANCD2 monoubiquitination to the detection of DNA damage at the replication fork will be determined. ShRNA-mediated suppression of these proteins in primary human CD34+ cells, and expression of mutants in an immortalized myeloid precursor line, will be utilized. Whether these DNA damage sensors prevent chromosomal instability and apoptosis in response to MMC will also be determined. 2) Determine whether defects in FANCD2 monoubiquitination and the assembly of FANCD2 foci results in chromosomal instability and sensitivity to MMC in CD34+ hematopoietic stem/progenitor cells. FANCD2 monoubiquitination will be inhibited by shRNA-mediated suppression of FANCA. Also, mechanisms involved in the recruitment of FANCD2 to blocked replication forks will be elucidated using real-time microscopy in cells reconstituted with EGFP- FANCD2. PROJECT NARRATIVE It is increasingly clear that alterations in some Fanconi anemia pathway proteins are involved in some spontanous cancers seen in the general population. Thus the studies described in this application may shed new light on both normal and abnormal stem cell function and on cancer formation.

摘要范可尼贫血（FA）是一种多基因疾病，导致进行性骨髓衰竭以及骨髓增生异常综合征和白血病的强烈倾向。FA蛋白是通过一种很大程度上未知的机制参与细胞对DNA损伤的反应。核 FANCD 2的单泛素化需要至少8个FA蛋白的复合物。 FANCD 2的单泛素化是抵抗交联剂丝裂霉素C所必需的。的 ATR检查点激酶还调节FANCD 2单泛素化，并可能与FANCD 2的单泛素化有关。 FANCD 2可以检测复制叉处的DNA损伤。本研究的目的是了解FANCD 2单泛素化的调控和功能，从而更好地了解FA蛋白在促进正常造血中的集体作用。某些FA 蛋白质在一般人群的自发性癌症中发生突变，因此这些研究也与了解癌症的发展有关。研究的具体目标如下：如下所示： 1)描述FANCD 2单泛素化的ATR依赖性调节机制。 MCM 7和Rad 17以及Rad 9如何以及是否合作耦合FANCD 2 将确定单泛素化对检测复制叉处的DNA损伤的影响。 ShRNA介导的这些蛋白在原代人CD 34+细胞中的抑制，将利用永生化髓样前体细胞系中的突变体。这些DNA 损伤传感器防止染色体不稳定性，并且响应MMC的细胞凋亡也将被确定。 2)确定FANCD 2单泛素化和FANCD 2焦点组装中的缺陷是否导致CD 34+造血细胞中染色体不稳定和对MMC敏感干/祖细胞。FANCD 2单泛素化将被shRNA介导的对FANCA的镇压。此外，参与招募刚果民主共和国第二武装部队成员的机制也被阻断，将使用实时显微镜在用EGFP重建的细胞中阐明复制叉， FANCD 2.项目叙述越来越清楚的是，一些范可尼贫血途径蛋白的改变参与了一些常见于普通人群的自发性癌症。因此，本文中描述的研究应用可能会对正常和异常的干细胞功能以及癌症有新的认识阵

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

PALB2 (partner and localizer of BRCA2).

DOI：
10.4267/2042/69016
发表时间：
2018-04-01
期刊：
Atlas of genetics and cytogenetics in oncology and haematology
影响因子：
0
作者：
Hanenberg, Helmut;Andreassen, Paul R
通讯作者：
Andreassen, Paul R

SCML2 establishes the male germline epigenome through regulation of histone H2A ubiquitination.

DOI：
10.1016/j.devcel.2015.01.014
发表时间：
2015-03-09
期刊：
DEVELOPMENTAL CELL
影响因子：
11.8
作者：
Hasegawa, Kazuteru;Sin, Ho-Su;Maezawa, So;Broering, Tyler J.;Kartashov, Andrey V.;Alavattam, Kris G.;Ichijima, Yosuke;Zhang, Fan;Bacon, W. Clark;Greis, Kenneth D.;Andreassen, Paul R.;Barski, Artem;Namekawa, Satoshi H.
通讯作者：
Namekawa, Satoshi H.

Complementation of hypersensitivity to DNA interstrand crosslinking agents demonstrates that XRCC2 is a Fanconi anaemia gene.

DOI：
10.1136/jmedgenet-2016-103847
发表时间：
2016-10
期刊：
Journal of medical genetics
影响因子：
4
作者：
Park JY;Virts EL;Jankowska A;Wiek C;Othman M;Chakraborty SC;Vance GH;Alkuraya FS;Hanenberg H;Andreassen PR
通讯作者：
Andreassen PR

PALB2 functionally connects the breast cancer susceptibility proteins BRCA1 and BRCA2.