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CAS9 is a genome mutator by directly disrupting DNA-PK dependent DNA repair pathway

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Protein & Cell 2020年第5期11卷 352-365页

作者： Shuxiang Xu Jinchul Kim Qingshuang Tang Qu Chen Jingfeng Liu Yang Xu Xuemei Fu Cancer Research Institute Guangdong Provincial Key Laboratory of Cancer ImmunotherapySchool of Basic Medical SciencesSouthern Medical UniversityGuangzhou 510515China The Eighth Affiliated Hospital Sun Yat-sen UniversityShenzhen 518033China Division of Biological Sciences University of CaliforniaSan Diego9500 Gilman DriveLa JollaCA 92093USA Shenzhen Children’s Hospital Shenzhen 518026China

With its high efficiency for site-specific genome editing and easy manipulation,the clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR associated protein 9(CAS9)system has become the most widely used gene editing technology in biomedical *** addition,significant progress has been made for the clinical development of CRISPR/CAS9 based gene therapies of human diseases,several of which are entering clinical *** we report that CAS9 protein can function as a genome mutator independent of any exogenous guide RNA(gRNA)in human cells,promoting genomic DNA double-stranded break(DSB)damage and genomic ***9 interacts with the KU86 subunit of the DNA-dependent protein kinase(DNA-PK)complex and disrupts the interaction between KU86 and its kinase subunit,leading to defective DNA-PK-dependent repair of DNA DSB damage via non-homologous end-joining(NHEJ)***9 is a CAS9 variant with potentially higher fidelity and broader compatibility,and dCAS9 is a CAS9 variant without nuclease *** show that XCAS9 and dCAS9 also interact with KU86 and disrupt DNA DSB *** the critical roles of DNA-PK in maintaining genomic stability and the pleiotropic impact of DNA DSB damage responses on cellular proliferation and survival,our findings caution the interpretation of data involving CRISPR/CAS9-based gene editing and raise serious safety concerns of CRISPR/CAS9 system in clinical application.

关键词： KEYWORDS CAS9 DNA-PK DNA double-stranded breaks genetic instability DNA repair

Alternative splicing of DNA damage response genes and gastrointestinal cancers

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World Journal of Gastroenterology 2014年第46期20卷 17305-17313页

作者： Bahityar Rahmutulla Kazuyuki Matsushita Fumio Nomura Department of Molecular Diagnosis Graduate School of MedicineChiba UniversityChiba 260-8670Japan Division of Laboratory Medicine Chiba University HospitalChiba 260-8670Japan

Alternative splicing,which is a common phenomenon in mammalian genomes,is a fundamental process of gene regulation and contributes to great protein *** splicing events not only occur in the normal gene regulation process but are also closely related to certain diseases including *** this review,we briefly demonstrate the concept of alternative splicing and DNA damage and describe the association of alternative splicing and cancer pathogenesis,focusing on the potential relationship of alternative splicing,DNA damage,and gastrointestinal *** will also discuss whether alternative splicing leads to genetic instability,which is considered to be a driving force for *** understanding of the role and mechanism of alternative splicing in tumorigenesis may provide new directions for future cancer studies.

关键词： Alternative splicing DNA damage Gastrointestinal cancer Mutation genetic instability

Mathematical modeling of female breast cancer in Japan

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International Journal of Biomathematics 2020年第4期13卷 33-47页

作者： Ahmed Nagah Asmaa Amer Xinan Zhang School of Mathematics and Statistics Central China Normal UniversityWuhan 430079P.R.China Mathematics Department Faculty of Science Zagazig UniversityZagazigEgypt Mathematics Department Faculty of Science Menoufia UniversityEgypt

Cancer incidence rates are significantly diferent all over the *** cancer is affected by many factors,the most important being genetics and *** aim of this paper is to study the mutation mechanisms of breast cancer for Japanese women by fitting the incidence data of three high-quality population areas in Japan from 1985 to *** achieve this goal,we have set up multi-stage models within the mathematical model of Moolgavkar,Venzon,and *** models take both mutation rates and clonal expansion rates as parameters in each compartment into *** on our simulation outcomes,two to twelve driver mutations are sufficient in the pathway to female breast cancer in *** the other hand,a previous study demonstrated that breast cancer in American women requires two to fourteen gene mutations to get a cancerous ***,the 3-stage mat hematical model is the optimal model as it fits clinical data very nicely for all affected cases of females in Japan and the *** genetic instability has a promincnt effect on the tumorigenesis of Japanese females caused by the first four driver *** calculated results for Japanese women are compared with previous works for American women.

关键词： Breast cancer multi-stage models genetic instability chi-square test

Micronucleus analysis in patients with colorectal adenocarcinoma and colorectal polyps

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World Journal of Gastroenterology 2008年第44期14卷 6835-6839页

作者： Ali Karaman Dogan Nas■r Binici Mehmet E■ref Kabalar Züleyha ■al■ku■u Department of Medical genetics Erzurum Training and Research HospitalErzurum 25240Turkey Department of Internal Medicine Erzurum Training and Research HospitalErzurum 25240Turkey Department of Pathology Erzurum Training and Research HospitalErzurum 25240Turkey Department of Medical Oncology Erzurum Training and Research HospitalErzurum 25240Turkey

AIM:To determine,by counting micronucleus (MN) frequencies,whether chromosomal or DNA damage have an effect on the pathogenesis of early colorectal adenocarcinoma (CRC). METHODS:We analyzed MN frequencies in 21 patients with CRC,24 patients with colon polyps [10 neoplastic polyps (NP) and 14 non-neoplastic polyps (NNP)] and 20 normal controls. RESULTS:MN frequency was significantly increased in CRC patients and in NP patients compared with controls (3.72 ± 1.34,3.58 ± 1.21 vs 1.97 ± 0.81,P 0.05). Similarly,there was no difference in the MN frequency between NNP patients (2.06 ± 0.85) and controls (P > 0.05). CONCLUSION:Our results suggest increased chromosome/DNA instabilities may be associated with the pathogenesis of early CRC.

关键词： Colorectal adenocarcinoma Colon polyp Micronucleus genetic instability

Conditional Mutations in Drosophila

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Journal of Life Sciences 2011年第3期5卷 224-240页

作者： Boris F. Chadov Nina B. Fedorova Eugenia V. Chadova Helena A. Khotskina Institute of Cytology and genetics Siberian Department of Russian Academy of Sciences Novosibirsk 630090 Russia

The aim of this study was to obtain unusual mutations called conditional. The mutations manifest in some, not all representatives of a species. Collections of these mutations in chromosomes X, 2, and 3 of Drosophila melanogaster were established. Sex of fly or chromosomal rearrangement was the conditions providing ＂manifestation-non manifestation＂ of these mutations. The mutations differ from the usual by a set of properties. The salient differences in addition to conditional manifestation include： manifestation dependence on the spatial arrangement of chromosomal material in the genome, parental effects （maternal or paternal） of the mutant, capacity for transferring the genome from stable to unstable state. It is suggested that conditional mutations are mutant variants of Drosophila regulatory genes contained by the large Genomic Regulatory Network of Drosophila. Thus, the genes of this category can be detected by using special breeding procedures, mutations of these genes have unusual manifestation.

关键词： Conditional mutation penetrance modification morphosis dominant lethal genetic instability energy dissipation Drosophila melanogaster.