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The fanconi anemia pathway and DNA interstrand cross-link repair

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Protein & Cell 2011年第9期2卷 704-711页

作者： Xiaoyu Su Jun Huang Life Sciences Institute Zhejiang UniversityHangzhou 310058China

fanconi anemia(FA)is an autosomal or X-linked recessive disorder characterized by chromosomal instability,bone marrow failure,cancer susceptibility,and a profound sensitivity to agents that produce DNA interstrand cross-link(ICL).To date,15 genes have been identified that,when mutated,result in FA or an FA-like syndrome.It is believed that cellular resistance to DNA interstrand cross-linking agents requires all 15 FA or FAlike proteins.Here,we review our current understanding of how these FA proteins participate in ICL repair and discuss the molecular mechanisms that regulate the FA pathway to maintain genome stability.

关键词： fanconi anemia DNA interstrand crosslink repair FANCD2-FANCI mono-ubiquitylation chromosomal instability

Diagnosis of fanconi anemia in children with atypical clinical features： a primary study

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Chinese Medical Journal 2013年第23期126卷 4483-4486页

作者： LIU Rong HU Tao LI Jun-hui LIANG Chao GU Wei-yue SHI Xiao-dong WANG Hong-xing Department of Hematology Capital Institute of Pediatrics Beijing 100020 China Beijing Hightrust Diagnostics Beijing 100044 China Joy Orient Translational Medicine Research Center Co. Ltd. Beijing 100088 China Beijing Anding Hospital Capital Medical University Beijing 100088China

Background fanconi anemia is a severe congenital disorder associated with mutations in a cluster of genes responsible for DNA repair.Arriving at an accurate and timely diagnosis can be difficult in cases of fanconi anemia with atypical clinical features.It is very important to increase the rate of accurate diagnosis for such cases in a clinical setting.The purpose of this study is to explore the clinical diagnosis of fanconi anemia in children with atypical clinical features.Methods Six cases of fanconi anemia with atypical clinical features were enrolled in the study,and their clinical features were recorded,their FANCA gene transcription was assessed by RT-PCR,and FANCA mutations and the ubiquitination of FANCD2 protein were analyzed using DNA sequencing and western blotting respectively.Results All six cases showed atypical clinical features including no apparent deformities,lack of response to immune therapy,and progressively increasing bone marrow failure.They also have significantly increased fetal hemoglobin,negative mitomycin-induced fracture test results,and carry a FANCA gene missense mutation.Single protein ubiquitination of FANCD2 was not observed in those patients.Conclusion The combination of clinical features,FANCA pathogenic gene mutation genotype and the absence of FANCD2 protein ubiquitination are helpful in the accurate and timely diagnosis of fanconi anemia in children.

关键词： fanconi anemia clinical features gene mutation FANCD2 protein

DNAH2 facilitates the homologous recombination repair of fanconi anemia pathway through modulating FANCD2 ubiquitination

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Blood Science 2021年第3期3卷 71-77页

作者： Lixian Chang Xingjie Gao Yuxia Wang Chunmin Huang Min Gao Xiaomin Wang Chao Liu Wenqi Wu Wenbin An Yang Wan Aoli Zhang Yingchi Zhang Weiping Yuan Xiaofan Zhu State Key Laboratory of Experimental Hematology National Clinical Research Center for Blood DiseasesInstitute of Hematology&Blood Diseases HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeTianjinChina Department of Biochemistry and Molecular Biology School of Basic Medical SciencesTianjin Medical UniversityTianjinChina Department of Hematology Myelodysplastic Syndromes Diagnosis and Therapy Centerthe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina Beijing Institute of Genomics Chinese Academy of Sciences(China National Center for Bioinformation)BeijingChina

fanconi anemia(FA),an X-linked genetic or autosomal recessive disease,exhibits complicated pathogenesis.Previously,we detected the mutated Dynein Axonemal Heavy Chain 2(DNAH2)gene in 2 FA cases.Herein,we further investigated the potential association between DNAH2 and the homologous recombination repair pathway of FA.The assays of homologous recombination repair,mitomycin C(MMC)sensitivity,immunofluorescence,and ubiquitination modification were performed in U2OS and DR-U2OS cell lines.In MMC-treated U2OS cells,the downregulation of the DNAH2 gene increased the sensitivity of cells to DNA inter-strand crosslinks.We also observed the reduced enrichment of FANCD2 protein to DNA damage sites.Furthermore,the ubiquitination modification level of FANCD2 was influenced by the deficiency of DNAH2.Thus,our results suggest that DNAH2 may modulate the cell homologous recombination repair partially by increasing the ubiquitination and the enrichment to DNA damage sites of FANCD2.DNAH2 may act as a novel co-pathogenic gene of FA patients.

关键词： DNAH2 FANCD2 fanconi anemia Homologous recombination Ubiquitination

Novel diagnostic approaches for fanconi anemia (FA) by single-cell sequencing and capillary nano-immunoassay

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Blood Science 2021年第1期3卷 20-25页

作者： Lixian Chang Xingjie Gao Guangzhen Ji Xuelian Cheng Yao Zou Tao Cheng Weiping Yuan Xiaofan Zhu State Key Laboratory of Experimental Hematology National Clinical Research Center for Blood DiseasesInstitute of Hematology&Blood Diseases HospitalChinese Academy of Medical Sciences&Peking Union Medical CollegeTianjin 300020China Department of Biochemistry and Molecular Biology School of Basic Medical SciencesTianjin Medical UniversityTianjin 300070China

Next-generation sequencing technology has been widely utilized for the diagnosis of fanconi anemia(FA).However,mixed cell sequencing and chimerism of FA patients may lead to unconfirmed genetic subtypes.Herein,we introduced two novel diagnostic methods,including single-cell sequencing and capillary nano-immunoassay.One FA case with FANCM c.4931G>A p.R1644Q and FANCD1 c.6325G>A p.V2109I was studied.The DNA of 28 cells was amplified and eight types of cells were observed after Sanger sequencing.There were two homozygous mutations(FANCM/FANCD1).Furthermore,the capillary nano-immunoassay was conducted to analyze the expression profile of FA-associated proteins.Abnormal FANCM and FANCD1 expressions simultaneously existed.This case was thus diagnosed as FA-D1/FA-M dual subtype.Compared with mixed cell sequencing,single-cell sequencing data shows more accuracy for the FA subtype evaluation,while the capillary nano-immunoassay is a good method to detect the expression profile of abnormal or modified FA protein.

关键词： Capillary nano-immunoassay FANCD1 FANCD2 FANCM fanconi anemia Single-cell sequencing