I completed my medical studies at the Karolinska Institute in Stockholm but have always been devoted to basic research. My longstanding interest is to understand fundamental DNA repair mechanisms in the fields of canc...I completed my medical studies at the Karolinska Institute in Stockholm but have always been devoted to basic research. My longstanding interest is to understand fundamental DNA repair mechanisms in the fields of cancer therapy, inherited human genetic disorders and ancient DNA. I initially measured DNA decay, including rates of base loss and cytosine deamination. I have dis- covered several important DNA repair proteins and determined their mechanisms of action. The discovery of uracil-DNA glycosylase defined a new category of repair enzymes with each specialized for different types of DNA damage. The base excision repair pathway was first reconstituted with human proteins in my group. Cell-free analysis for mammalian nucleotide excision repair of DNA was also developed in my laboratory. I found multiple distinct DNA ligases in mammalian cells, and led the first genetic and biochemical work on DNA ligases I, III and IV. I discovered the mam- malian exonucleases DNase III （TREX1） and IV （FEN1）. Interestingly, expression of TREXI was altered in some human autoimmune diseases. I also showed that the mutagenic DNA adduct O6-methylguanine （O6mG） is repaired without removing the guanine from DNA, identifying a sur- prising mechanism by which the methyl group is transferred to a residue in the repair protein itself. A further novel process of DNA repair discovered by my research group is the action of AlkB as an iron-dependent enzyme carrying out oxidative demethylation.展开更多
It was ever thought that genomic information is transmitted faithfully from generation to generation. But our current knowledge does not indicate that it is the case. For example, genomic variations can be generated f...It was ever thought that genomic information is transmitted faithfully from generation to generation. But our current knowledge does not indicate that it is the case. For example, genomic variations can be generated from DNA replication infidelity and unequal chromosome segregation. Natural decay of DNA molecules is also a fundamental source of changing genomic information. In addition, cellular and organismal exposure to exogenous genotoxic agents such as ultraviolet （UV） light, oxidative stress, chemical mutagens, and radiation can lead to a variety of modifications on DNA constituents, resulting in genome alterations. Fortunately, cells have evolved several response systems to tackle numerous DNA lesions in order to maintain their genome integrity. Among them, check- point control is probably the most well-known one. For exam- ple, checkpoint responds to replication stress, replication fork stalling, double-strand DNA breaks, and various other types of DNA lesions. Increasing experimental evidence indicates that genomic instability is probably the fundamental reason for carcinogenesis. Genomic instability is also found to be a main etiological factor of neurodegenerative diseases, aging, immunodeficiency, etc. Thus, to understand how cells regulate to maintain their genomic stability is of fundamental importance.展开更多
文摘I completed my medical studies at the Karolinska Institute in Stockholm but have always been devoted to basic research. My longstanding interest is to understand fundamental DNA repair mechanisms in the fields of cancer therapy, inherited human genetic disorders and ancient DNA. I initially measured DNA decay, including rates of base loss and cytosine deamination. I have dis- covered several important DNA repair proteins and determined their mechanisms of action. The discovery of uracil-DNA glycosylase defined a new category of repair enzymes with each specialized for different types of DNA damage. The base excision repair pathway was first reconstituted with human proteins in my group. Cell-free analysis for mammalian nucleotide excision repair of DNA was also developed in my laboratory. I found multiple distinct DNA ligases in mammalian cells, and led the first genetic and biochemical work on DNA ligases I, III and IV. I discovered the mam- malian exonucleases DNase III （TREX1） and IV （FEN1）. Interestingly, expression of TREXI was altered in some human autoimmune diseases. I also showed that the mutagenic DNA adduct O6-methylguanine （O6mG） is repaired without removing the guanine from DNA, identifying a sur- prising mechanism by which the methyl group is transferred to a residue in the repair protein itself. A further novel process of DNA repair discovered by my research group is the action of AlkB as an iron-dependent enzyme carrying out oxidative demethylation.
文摘It was ever thought that genomic information is transmitted faithfully from generation to generation. But our current knowledge does not indicate that it is the case. For example, genomic variations can be generated from DNA replication infidelity and unequal chromosome segregation. Natural decay of DNA molecules is also a fundamental source of changing genomic information. In addition, cellular and organismal exposure to exogenous genotoxic agents such as ultraviolet （UV） light, oxidative stress, chemical mutagens, and radiation can lead to a variety of modifications on DNA constituents, resulting in genome alterations. Fortunately, cells have evolved several response systems to tackle numerous DNA lesions in order to maintain their genome integrity. Among them, check- point control is probably the most well-known one. For exam- ple, checkpoint responds to replication stress, replication fork stalling, double-strand DNA breaks, and various other types of DNA lesions. Increasing experimental evidence indicates that genomic instability is probably the fundamental reason for carcinogenesis. Genomic instability is also found to be a main etiological factor of neurodegenerative diseases, aging, immunodeficiency, etc. Thus, to understand how cells regulate to maintain their genomic stability is of fundamental importance.
