冯文毅博士
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研究项目和附属机构
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How do defects in DNA replication lead to genomic instability? This question bears on our understanding of a wide spectrum of human diseases, 包括染色体脆性, 癌症, 神经退化, 甚至是自身免疫性疾病. Eukaryotic chromosomal DNA replication is a process that is at once robust and vulnerable. It is accurate and able to withstand environmental stress, such as DNA damage and replication impediments, 通过高度进化的检查点机制. 然而复制的行为本身, if executed in an untimely or uncoordinated fashion, 会导致基因组不稳定吗.
My laboratory is interested in understanding the mechanisms of genomic instability induced by DNA replication stress. Previous work including ours had established that replication stress induces extensive single-stranded DNA formation at replication forks, which ultimately results in double stranded DNA breaks (DSBs). We further demonstrated that DSBs occur more frequently at the genes that are subject to transcription induction by the drug used to elicit replication stress-for instance-hydroxyurea, 核糖核苷酸还原酶的抑制剂. This suggests that replication-transcription collision underlies DSB formation. We are currently more rigorously testing the hypothesis by using a variety of replication stress-inducing drugs to induce, 系统地绘制, 模式生物中的dsb, 酿酒cerevisiase. Our hypothesis would predict that the genomic locations that are most susceptible to DSBs are correlated with heightened gene expression due to drug induction. We are performing deep-sequencing experiments to simultaneously query the genome for DSB formation by Break-seq and gene expression by RNA-seq. We are also performing experiments to address if the relative speeds of the replication and transcription machineries during collisions play a role in DSB formation.
Equipped with the powerful tool of Break-seq we are also mapping replication stress-induced DSBs in mammalian cells, 称为染色体脆弱位点, which play an important role in genomic rearrangements and the genesis of a wide range of human diseases including 癌症. We have systematically identifying DSBs in cells derived from patients with the Fragile X Syndrome (FXS), 最常见的遗传性智力低下. 我们在FXS模型中观察到这一点, replication stress-induced CFSs are preferentially localized to the R-loop forming sequences (RLFSs), which are cis-elements with high probability of forming DNA:RNA hybrids during transcription. This led to the discovery that the protein that is deficient in the FXS, FMRP, has a novel function in genome maintenance by preventing R-loop formation during replication-transcription conflict, thus shedding light on the underlying etiological basis for FXS. Our current endeavors take us beyond this disease model to examine different 癌症 genomes to discover new "at-risk" gene such as novel tumor suppressors.
选择出版物:
冯女士. Chakraborty A. (2017) Fragility Extraordinaire: Unsolved mysteries of chromosome fragile sites. 生物医学杂志. 1042:489-526. doi: 10.1007/978-981-10-6955-0_21.
冯女士. (2016) Mec1/ATR, the Program Manager of Nucleic Acids Inc. 基因(巴塞尔). 8(1). pii: E10汽油. doi: 10.3390 / genes8010010. 审查.
彭军，冯伟. (2016) Incision of damaged DNA in the presence of an impaired Smc5/6 complex imperils genome stability. 核酸类. pii: gkw720. [印前Epub]
Hang LE, Peng J, Tan W, Szakal B, Menolfi D, Sheng Z, Lobachev K, Branzei D, 冯女士, Zhao X. (2015) Rtt107 is a multi-functional scaffold supporting replication progression with partner SUMO and ubiquitin ligases. 摩尔细胞. 60:268-79.
Hoffman EA, McCulley A, Haarer B, Arnak R, 冯女士. (2015) Break-seq reveals hydroxyurea-induced chromosome fragility as a result of unscheduled conflict between DNA replication and transcription. 基因组Res. 25:401-12.
彭建明. K. 冯伟，Raghuraman. (2014) Analysis of ssDNA gaps and DSBs in genetically unstable yeast cultures. 方法:. 1170:501-15.
彭建明. K. 冯伟，Raghuraman. (2014) Analysis of replication timing using synchronized budding yeast cultures. 方法:. 1170:477-99.
McCulley A, Haarer B, Viggiano S, Karchin J, 冯女士. (2014) Chemical suppression of defects in mitotic spindle assembly, 氧化还原控制, 羟基脲合成甾醇. G3. 4(1):39-48.
冯女士*, Di Rienzi S, Raghuraman M K, Brewer B J. (2011) Replication stress-induced chromosome breakage is correlated with replication fork progression and is preceded by single-stranded DNA formation. G3. 1(5):327-35. *通讯作者.
冯女士, Bachant J, Collingwood D, Raghuraman M K, Brewer B J. (2009) Centromere replication timing determines different forms of genomic instabilit in Saccharomyces cerevisiae checkpoint mutants during replication stress. 遗传学. 183(4):1249-60.
冯女士, Collingwood D, Boeck M E, Fox L, Alvino G, Fangman W L, Raghuraman M K, Brewer B J. (2006) Genomic mapping of single-stranded DNA in hydroxyurea-challenged yeasts identifies origins of replication. 自然细胞生物学. 8(2):148-55.