Genome-wide high-resolution mapping of mitotic DNA synthesis sites and common fragile sites by direct sequencing  

作　　者：Fang Ji Hongwei Liao Sheng Pan Liujian Ouyang Fang Jia Zaiyang Fu Fengjiao Zhang Xinwei Geng Xinming Wang Tingting Li Shuangying Liu Madiha Zahra Syeda Haixia Chen Wen Li Zhihua Chen Huahao Shen Songmin Ying 

机构地区：[1]Department of Pharmacology&Department of Respiratory and Critical Care Medicine of the Second Affiliated Hospital,Zhejiang University School of Medicine,Key Laboratory of Respiratory Disease of Zhejiang Province,Hangzhou,Zhejiang,310009,China [2]Chu Kochen Honors College of Zhejiang University,Hangzhou,Zhejiang,China [3]School of Life Sciences,Peking University,Beijing,100871,China [4]State Key Laboratory of Proteomics,National Center of Biomedical Analysis,Institute of Basic Medical Sciences,Beijing,100850,China [5]Key Laboratory of Respiratory Disease of Zhejiang Province,Department of Respiratory and Critical Care Medicine,Second Affiliated Hospital of Zhejiang University School of Medicine,Hangzhou,Zhejiang,310009,China [6]State Key Laboratory of Respiratory Diseases,Guangzhou,Guangdong,510120,China

出　　处：《Cell Research》2020年第11期1009-1023,共15页细胞研究（英文版）

基　　金：This work was supported by grants to Songmin Ying from the Ministry of Science and Technology of China(2016YFA0100301);the National Natural Science Foundation of China(81870007,81920108001);the Zhejiang Provincial Natural Science Foundation(LD19H160001);the Zhejiang Provincial Program for the Cultivation of High-Level Innovative Health Talents(2016-63).

摘　　要：Common fragile sites(CFSs)are genomic loci prone to the formation of breaks or gaps on metaphase chromosomes.They are hotspots for chromosome rearrangements and structural variations,which have been extensively implicated in carcinogenesis,aging,and other pathological processes.Although many CFSs were identified decades ago,a consensus is still lacking for why they are particularly unstable and sensitive to replication perturbations.This is in part due to the lack of high-resolution mapping data for the vast majority of the CFSs,which has hindered mechanistic interrogations.Here,we seek to map human CFSs with high resolution on a genome-wide scale by sequencing the sites of mitotic DNA synthesis(MiDASeq)that are specific for CFSs.We generated a nucleotide-resolution atlas of MiDAS sites(MDSs)that covered most of the known CFSs,and comprehensively analyzed their sequence characteristics and genomic features.Our data on MDSs tallied well with long-standing hypotheses to explain CFS fragility while highlighting the contributions of late replication timing and large transcription units.Notably,the MDSs also encompassed most of the recurrent double-strand break clusters previously identified in mouse neural stem/progenitor cells,thus bridging evolutionarily conserved break points across species.Moreover,MiDAseq provides an important resource that can stimulate future research on CFSs to further unravel the mechanisms and biological relevance underlying these labile genomic regions.

关 键 词：synthesis RESOLUTION BRIDGING 

分 类 号：Q523[生物学—生物化学]