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helicases couple the hydrolysis of nucleotide or deoxynucleotide triphosphate to duplex unwinding (1). Coordination of a set of subactivities including nucleotide binding, DNA binding and ATP hydrolysis is required for unwinding of duplex DNA (1,2). The hexameric helicases, to which minichromosome maintenance (Mcm) helicase belongs, are known to assemble a ring-like structure (3–5). Whereas most of DNA helicases of this group, including simian virus 40 large T-antigen (6), Escherichia coli DnaB (7) and Archaeal Mcm (4,8,9), are composed of a single subunit, the active eukaryotic Mcm helicases are composed of two trimeric Mcm4/6/7 proteins (10–14).\nAll the six Mcm 2–7 proteins contain highly conserved DNA-dependent ATPase motifs in their central regions (15,16). Among the several stable subcomplexes which MCM proteins can generate, only the Mcm4/6/7 complex has been shown to possess an intrinsic DNA helicase activity (10–14,17–18). While Mcm4, Mcm6 and Mcm7 proteins make distinct contribution to its helicase activity (11–13), Mcm2 or Mcm3/5 inhibit the helicase activity of the Mcm4/6/7 complex by converting its double trimer structure into a heterotetramer or heteropentamer, respectively (3,11). Chromatin immunoprecipitation assays and genetic characterization in Saccharomyces cerevisiae strongly suggested that Mcm is involved not only in initiation but also in the DNA chain elongation stage as a replicative helicase (19,20). Consistent with this notion, the processivity of the Schizosaccharomyces pombe and mouse Mcm4/6/7 complexes is significantly stimulated on forked DNA structures and it can unwind duplex DNA of 400–500 bp (13,14). Mcm4/6/7 binds to fork and bubble structures in an ATP-dependent manner, and generates a double-hexameric complex, as was shown for T-antigen (13,14,21). Recently, we reported that the helicase and ATP hydrolysis activities of mammalian Mcm4/6/7 are specifically activated by single-stranded DNA containing stretches of thymine residues and proposed a novel model that Mcm may play a crucial role in selection of replication origins in higher eukaryotes (13).\nIn this report, in order to clarify the mode of action of the Mcm helicase and obtain insight into how it may function at the replication forks in vivo, we have conducted detailed analyses of helicase action and DNA binding of mouse Mcm4/6/7 helicase using various forked and bubble substrate DNAs. We specifically addressed sequence requirement for the Mcm helicase activation, mode of interaction with DNA substrates and whether the thymine sequences are required for continuous activation of Mcm helicase during the unwinding process. The results indicate that mammalian Mcm4/6/7 primarily binds to single-stranded DNA region, and that the extent of helicase activation is related to the thymine content of the single-stranded segment. Unexpectedly, Mcm4/6/7 helicase is not capable of efficiently unwinding the GC-rich duplex segment, suggesting that some other mechanism may be required for completion of replication of the entire genome."}

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helicases couple the hydrolysis of nucleotide or deoxynucleotide triphosphate to duplex unwinding (1). Coordination of a set of subactivities including nucleotide binding, DNA binding and ATP hydrolysis is required for unwinding of duplex DNA (1,2). The hexameric helicases, to which minichromosome maintenance (Mcm) helicase belongs, are known to assemble a ring-like structure (3–5). Whereas most of DNA helicases of this group, including simian virus 40 large T-antigen (6), Escherichia coli DnaB (7) and Archaeal Mcm (4,8,9), are composed of a single subunit, the active eukaryotic Mcm helicases are composed of two trimeric Mcm4/6/7 proteins (10–14).\nAll the six Mcm 2–7 proteins contain highly conserved DNA-dependent ATPase motifs in their central regions (15,16). Among the several stable subcomplexes which MCM proteins can generate, only the Mcm4/6/7 complex has been shown to possess an intrinsic DNA helicase activity (10–14,17–18). While Mcm4, Mcm6 and Mcm7 proteins make distinct contribution to its helicase activity (11–13), Mcm2 or Mcm3/5 inhibit the helicase activity of the Mcm4/6/7 complex by converting its double trimer structure into a heterotetramer or heteropentamer, respectively (3,11). Chromatin immunoprecipitation assays and genetic characterization in Saccharomyces cerevisiae strongly suggested that Mcm is involved not only in initiation but also in the DNA chain elongation stage as a replicative helicase (19,20). Consistent with this notion, the processivity of the Schizosaccharomyces pombe and mouse Mcm4/6/7 complexes is significantly stimulated on forked DNA structures and it can unwind duplex DNA of 400–500 bp (13,14). Mcm4/6/7 binds to fork and bubble structures in an ATP-dependent manner, and generates a double-hexameric complex, as was shown for T-antigen (13,14,21). Recently, we reported that the helicase and ATP hydrolysis activities of mammalian Mcm4/6/7 are specifically activated by single-stranded DNA containing stretches of thymine residues and proposed a novel model that Mcm may play a crucial role in selection of replication origins in higher eukaryotes (13).\nIn this report, in order to clarify the mode of action of the Mcm helicase and obtain insight into how it may function at the replication forks in vivo, we have conducted detailed analyses of helicase action and DNA binding of mouse Mcm4/6/7 helicase using various forked and bubble substrate DNAs. We specifically addressed sequence requirement for the Mcm helicase activation, mode of interaction with DNA substrates and whether the thymine sequences are required for continuous activation of Mcm helicase during the unwinding process. The results indicate that mammalian Mcm4/6/7 primarily binds to single-stranded DNA region, and that the extent of helicase activation is related to the thymine content of the single-stranded segment. Unexpectedly, Mcm4/6/7 helicase is not capable of efficiently unwinding the GC-rich duplex segment, suggesting that some other mechanism may be required for completion of replication of the entire genome."}

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helicases couple the hydrolysis of nucleotide or deoxynucleotide triphosphate to duplex unwinding (1). Coordination of a set of subactivities including nucleotide binding, DNA binding and ATP hydrolysis is required for unwinding of duplex DNA (1,2). The hexameric helicases, to which minichromosome maintenance (Mcm) helicase belongs, are known to assemble a ring-like structure (3–5). Whereas most of DNA helicases of this group, including simian virus 40 large T-antigen (6), Escherichia coli DnaB (7) and Archaeal Mcm (4,8,9), are composed of a single subunit, the active eukaryotic Mcm helicases are composed of two trimeric Mcm4/6/7 proteins (10–14).\nAll the six Mcm 2–7 proteins contain highly conserved DNA-dependent ATPase motifs in their central regions (15,16). Among the several stable subcomplexes which MCM proteins can generate, only the Mcm4/6/7 complex has been shown to possess an intrinsic DNA helicase activity (10–14,17–18). While Mcm4, Mcm6 and Mcm7 proteins make distinct contribution to its helicase activity (11–13), Mcm2 or Mcm3/5 inhibit the helicase activity of the Mcm4/6/7 complex by converting its double trimer structure into a heterotetramer or heteropentamer, respectively (3,11). Chromatin immunoprecipitation assays and genetic characterization in Saccharomyces cerevisiae strongly suggested that Mcm is involved not only in initiation but also in the DNA chain elongation stage as a replicative helicase (19,20). Consistent with this notion, the processivity of the Schizosaccharomyces pombe and mouse Mcm4/6/7 complexes is significantly stimulated on forked DNA structures and it can unwind duplex DNA of 400–500 bp (13,14). Mcm4/6/7 binds to fork and bubble structures in an ATP-dependent manner, and generates a double-hexameric complex, as was shown for T-antigen (13,14,21). Recently, we reported that the helicase and ATP hydrolysis activities of mammalian Mcm4/6/7 are specifically activated by single-stranded DNA containing stretches of thymine residues and proposed a novel model that Mcm may play a crucial role in selection of replication origins in higher eukaryotes (13).\nIn this report, in order to clarify the mode of action of the Mcm helicase and obtain insight into how it may function at the replication forks in vivo, we have conducted detailed analyses of helicase action and DNA binding of mouse Mcm4/6/7 helicase using various forked and bubble substrate DNAs. We specifically addressed sequence requirement for the Mcm helicase activation, mode of interaction with DNA substrates and whether the thymine sequences are required for continuous activation of Mcm helicase during the unwinding process. The results indicate that mammalian Mcm4/6/7 primarily binds to single-stranded DNA region, and that the extent of helicase activation is related to the thymine content of the single-stranded segment. Unexpectedly, Mcm4/6/7 helicase is not capable of efficiently unwinding the GC-rich duplex segment, suggesting that some other mechanism may be required for completion of replication of the entire genome."}

{"project":"2_test","denotations":[{"id":"15917436-10966472-76775476","span":{"begin":116,"end":117},"obj":"10966472"},{"id":"15917436-10966472-76775477","span":{"begin":261,"end":262},"obj":"10966472"},{"id":"15917436-8381400-76775478","span":{"begin":263,"end":264},"obj":"8381400"},{"id":"15917436-10884341-76775479","span":{"begin":397,"end":398},"obj":"10884341"},{"id":"15917436-14566326-76775479","span":{"begin":397,"end":398},"obj":"14566326"},{"id":"15917436-12548282-76775479","span":{"begin":397,"end":398},"obj":"12548282"},{"id":"15917436-12774115-76775480","span":{"begin":491,"end":492},"obj":"12774115"},{"id":"15917436-12206765-76775481","span":{"begin":518,"end":519},"obj":"12206765"},{"id":"15917436-14566326-76775482","span":{"begin":539,"end":540},"obj":"14566326"},{"id":"15917436-10611290-76775483","span":{"begin":541,"end":542},"obj":"10611290"},{"id":"15917436-10677495-76775484","span":{"begin":543,"end":544},"obj":"10677495"},{"id":"15917436-9305914-76775485","span":{"begin":665,"end":667},"obj":"9305914"},{"id":"15917436-10567526-76775485","span":{"begin":665,"end":667},"obj":"10567526"},{"id":"15917436-12207017-76775485","span":{"begin":665,"end":667},"obj":"12207017"},{"id":"15917436-14609960-76775485","span":{"begin":665,"end":667},"obj":"14609960"},{"id":"15917436-11136247-76775485","span":{"begin":665,"end":667},"obj":"11136247"},{"id":"15917436-10872463-76775486","span":{"begin":781,"end":783},"obj":"10872463"},{"id":"15917436-12045100-76775487","span":{"begin":784,"end":786},"obj":"12045100"},{"id":"15917436-9305914-76775488","span":{"begin":948,"end":950},"obj":"9305914"},{"id":"15917436-10567526-76775488","span":{"begin":948,"end":950},"obj":"10567526"},{"id":"15917436-12207017-76775488","span":{"begin":948,"end":950},"obj":"12207017"},{"id":"15917436-14609960-76775488","span":{"begin":948,"end":950},"obj":"14609960"},{"id":"15917436-11136247-76775488","span":{"begin":948,"end":950},"obj":"11136247"},{"id":"15917436-9214646-76775489","span":{"begin":954,"end":956},"obj":"9214646"},{"id":"15917436-10770926-76775489","span":{"begin":954,"end":956},"obj":"10770926"},{"id":"15917436-10567526-76775490","span":{"begin":1050,"end":1052},"obj":"10567526"},{"id":"15917436-12207017-76775490","span":{"begin":1050,"end":1052},"obj":"12207017"},{"id":"15917436-14609960-76775490","span":{"begin":1050,"end":1052},"obj":"14609960"},{"id":"15917436-10884341-76775491","span":{"begin":1224,"end":1225},"obj":"10884341"},{"id":"15917436-10567526-76775492","span":{"begin":1226,"end":1228},"obj":"10567526"},{"id":"15917436-9335335-76775493","span":{"begin":1458,"end":1460},"obj":"9335335"},{"id":"15917436-10834843-76775494","span":{"begin":1461,"end":1463},"obj":"10834843"},{"id":"15917436-14609960-76775495","span":{"begin":1671,"end":1673},"obj":"14609960"},{"id":"15917436-11136247-76775496","span":{"begin":1674,"end":1676},"obj":"11136247"},{"id":"15917436-14609960-76775497","span":{"begin":1822,"end":1824},"obj":"14609960"},{"id":"15917436-11136247-76775498","span":{"begin":1825,"end":1827},"obj":"11136247"},{"id":"15917436-9765408-76775499","span":{"begin":1828,"end":1830},"obj":"9765408"},{"id":"15917436-14609960-76775500","span":{"begin":2134,"end":2136},"obj":"14609960"}],"text":"INTRODUCTION\nDNA helicases couple the hydrolysis of nucleotide or deoxynucleotide triphosphate to duplex unwinding (1). Coordination of a set of subactivities including nucleotide binding, DNA binding and ATP hydrolysis is required for unwinding of duplex DNA (1,2). The hexameric helicases, to which minichromosome maintenance (Mcm) helicase belongs, are known to assemble a ring-like structure (3–5). Whereas most of DNA helicases of this group, including simian virus 40 large T-antigen (6), Escherichia coli DnaB (7) and Archaeal Mcm (4,8,9), are composed of a single subunit, the active eukaryotic Mcm helicases are composed of two trimeric Mcm4/6/7 proteins (10–14).\nAll the six Mcm 2–7 proteins contain highly conserved DNA-dependent ATPase motifs in their central regions (15,16). Among the several stable subcomplexes which MCM proteins can generate, only the Mcm4/6/7 complex has been shown to possess an intrinsic DNA helicase activity (10–14,17–18). While Mcm4, Mcm6 and Mcm7 proteins make distinct contribution to its helicase activity (11–13), Mcm2 or Mcm3/5 inhibit the helicase activity of the Mcm4/6/7 complex by converting its double trimer structure into a heterotetramer or heteropentamer, respectively (3,11). Chromatin immunoprecipitation assays and genetic characterization in Saccharomyces cerevisiae strongly suggested that Mcm is involved not only in initiation but also in the DNA chain elongation stage as a replicative helicase (19,20). Consistent with this notion, the processivity of the Schizosaccharomyces pombe and mouse Mcm4/6/7 complexes is significantly stimulated on forked DNA structures and it can unwind duplex DNA of 400–500 bp (13,14). Mcm4/6/7 binds to fork and bubble structures in an ATP-dependent manner, and generates a double-hexameric complex, as was shown for T-antigen (13,14,21). Recently, we reported that the helicase and ATP hydrolysis activities of mammalian Mcm4/6/7 are specifically activated by single-stranded DNA containing stretches of thymine residues and proposed a novel model that Mcm may play a crucial role in selection of replication origins in higher eukaryotes (13).\nIn this report, in order to clarify the mode of action of the Mcm helicase and obtain insight into how it may function at the replication forks in vivo, we have conducted detailed analyses of helicase action and DNA binding of mouse Mcm4/6/7 helicase using various forked and bubble substrate DNAs. We specifically addressed sequence requirement for the Mcm helicase activation, mode of interaction with DNA substrates and whether the thymine sequences are required for continuous activation of Mcm helicase during the unwinding process. The results indicate that mammalian Mcm4/6/7 primarily binds to single-stranded DNA region, and that the extent of helicase activation is related to the thymine content of the single-stranded segment. Unexpectedly, Mcm4/6/7 helicase is not capable of efficiently unwinding the GC-rich duplex segment, suggesting that some other mechanism may be required for completion of replication of the entire genome."}