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results described in this manuscript reveal potentially important features of mammalian Mcm4/6/7 helicase, which is likely to be a key component of the eukaryotic replicative helicase. Prior to initiation of DNA replication, Mcm helicase may adopt a double hexameric complex at the partially melted origin region, and may catalyze concurrent unwinding of duplex DNA into both directions, while stably associated with the origins of DNA replication. This is similar to the T-antigen model originally proposed by Smelkova and Borowiec (21). We propose that, only when both hexamers are activated by the interacting thymine-rich sequences present within the melted region, the Mcm helicase is mobilized and initiation takes place. A crucial question is how these double hexameric helicase complexes are generated and turn into active helicases at the origins. This process would involve melting of duplex DNA, which may be facilitated by binding of preRC components in the context of proper chromatin structures, or by other unwinding factors including a topoisomerase or a newly identified Mcm8 helicase (34–36). It may also require association of fork-assisting proteins such as Cdc45 (37,38) as well as phosphorylation events by Cdk and Cdc7 kinases (39,40). One unexpected finding of this study is low helicase activity of Mcm4/6/7 on GC-rich duplex DNA. This, in conjunction with the low processivity of Mcm4/6/7 helicase, strongly indicates that the replicative helicase at the replication forks would require more than Mcm4/6/7 complex. During the processive unwinding of duplex DNA replication forks, Mcm4/6/7 may be further stimulated by interaction with other proteins, including remaining Mcm subunits, Cdc45 (37,38), GINS (41,42), DNA polymerase subunits (43), Mcm8 (35,36), etc. to become a truly processive and potent helicase capable of replicating the entire genome."}

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results described in this manuscript reveal potentially important features of mammalian Mcm4/6/7 helicase, which is likely to be a key component of the eukaryotic replicative helicase. Prior to initiation of DNA replication, Mcm helicase may adopt a double hexameric complex at the partially melted origin region, and may catalyze concurrent unwinding of duplex DNA into both directions, while stably associated with the origins of DNA replication. This is similar to the T-antigen model originally proposed by Smelkova and Borowiec (21). We propose that, only when both hexamers are activated by the interacting thymine-rich sequences present within the melted region, the Mcm helicase is mobilized and initiation takes place. A crucial question is how these double hexameric helicase complexes are generated and turn into active helicases at the origins. This process would involve melting of duplex DNA, which may be facilitated by binding of preRC components in the context of proper chromatin structures, or by other unwinding factors including a topoisomerase or a newly identified Mcm8 helicase (34–36). It may also require association of fork-assisting proteins such as Cdc45 (37,38) as well as phosphorylation events by Cdk and Cdc7 kinases (39,40). One unexpected finding of this study is low helicase activity of Mcm4/6/7 on GC-rich duplex DNA. This, in conjunction with the low processivity of Mcm4/6/7 helicase, strongly indicates that the replicative helicase at the replication forks would require more than Mcm4/6/7 complex. During the processive unwinding of duplex DNA replication forks, Mcm4/6/7 may be further stimulated by interaction with other proteins, including remaining Mcm subunits, Cdc45 (37,38), GINS (41,42), DNA polymerase subunits (43), Mcm8 (35,36), etc. to become a truly processive and potent helicase capable of replicating the entire genome."}

{"project":"craft-ca-core-dev","denotations":[{"id":"T10672","span":{"begin":359,"end":365},"obj":"SO:0000985"},{"id":"T10673","span":{"begin":425,"end":451},"obj":"SO:0000296"},{"id":"T10674","span":{"begin":436,"end":451},"obj":"GO:0006260"},{"id":"T10675","span":{"begin":478,"end":485},"obj":"CHEBI:59132"},{"id":"T10676","span":{"begin":659,"end":665},"obj":"GO:0032508"},{"id":"T10677","span":{"begin":678,"end":681},"obj":"GO:0042555"},{"id":"T10678","span":{"begin":781,"end":799},"obj":"GO:0033202"},{"id":"T10679","span":{"begin":852,"end":859},"obj":"SO:0000296"},{"id":"T10680","span":{"begin":888,"end":909},"obj":"GO:0032508"},{"id":"T10681","span":{"begin":899,"end":905},"obj":"SO:0000985"},{"id":"T10682","span":{"begin":950,"end":955},"obj":"GO:0005656"},{"id":"T10683","span":{"begin":992,"end":1001},"obj":"GO:0000785"},{"id":"T10684","span":{"begin":1092,"end":1096},"obj":"PR:000010250"},{"id":"T10685","span":{"begin":1150,"end":1154},"obj":"GO:0005657"},{"id":"T10686","span":{"begin":1182,"end":1187},"obj":"PR:000005215"},{"id":"T10687","span":{"begin":1241,"end":1245},"obj":"PR:000005218"},{"id":"T10688","span":{"begin":1328,"end":1332},"obj":"PR:000010246"},{"id":"T10689","span":{"begin":1328,"end":1336},"obj":"GO:0097373"},{"id":"T10690","span":{"begin":1348,"end":1354},"obj":"SO:0000985"},{"id":"T10691","span":{"begin":1410,"end":1414},"obj":"PR:000010246"},{"id":"T10692","span":{"begin":1410,"end":1418},"obj":"GO:0097373"},{"id":"T10693","span":{"begin":1457,"end":1468},"obj":"GO:0006260"},{"id":"T10694","span":{"begin":1485,"end":1496},"obj":"GO:0006260"},{"id":"T10695","span":{"begin":1485,"end":1502},"obj":"GO:0005657"},{"id":"T10696","span":{"begin":1527,"end":1531},"obj":"PR:000010246"},{"id":"T10697","span":{"begin":1527,"end":1543},"obj":"GO:0097373"},{"id":"T10698","span":{"begin":1580,"end":1586},"obj":"SO:0000985"},{"id":"T10699","span":{"begin":1587,"end":1602},"obj":"GO:0006260"},{"id":"T10700","span":{"begin":1587,"end":1608},"obj":"GO:0005657"},{"id":"T10701","span":{"begin":1610,"end":1614},"obj":"PR:000010246"},{"id":"T10702","span":{"begin":1610,"end":1618},"obj":"GO:0097373"},{"id":"T10703","span":{"begin":1701,"end":1704},"obj":"GO:0042555"},{"id":"T10704","span":{"begin":1715,"end":1720},"obj":"PR:000005215"},{"id":"T10705","span":{"begin":1730,"end":1734},"obj":"GO:0000811"},{"id":"T10706","span":{"begin":1774,"end":1778},"obj":"PR:000010250"},{"id":"T10707","span":{"begin":1853,"end":1864},"obj":"GO:0006260"},{"id":"T10708","span":{"begin":1876,"end":1882},"obj":"SO:0001026"},{"id":"T10662","span":{"begin":82,"end":91},"obj":"NCBITaxon:40674"},{"id":"T10663","span":{"begin":92,"end":96},"obj":"PR:000010246"},{"id":"T10664","span":{"begin":92,"end":100},"obj":"GO:0097373"},{"id":"T10665","span":{"begin":156,"end":166},"obj":"NCBITaxon:2759"},{"id":"T10666","span":{"begin":167,"end":178},"obj":"GO:0006260"},{"id":"T10667","span":{"begin":198,"end":227},"obj":"GO:0006270"},{"id":"T10668","span":{"begin":229,"end":232},"obj":"GO:0042555"},{"id":"T10669","span":{"begin":296,"end":302},"obj":"GO:0032508"},{"id":"T10670","span":{"begin":303,"end":309},"obj":"SO:0000296"},{"id":"T10671","span":{"begin":346,"end":369},"obj":"GO:0032508"}],"text":"The results described in this manuscript reveal potentially important features of mammalian Mcm4/6/7 helicase, which is likely to be a key component of the eukaryotic replicative helicase. Prior to initiation of DNA replication, Mcm helicase may adopt a double hexameric complex at the partially melted origin region, and may catalyze concurrent unwinding of duplex DNA into both directions, while stably associated with the origins of DNA replication. This is similar to the T-antigen model originally proposed by Smelkova and Borowiec (21). We propose that, only when both hexamers are activated by the interacting thymine-rich sequences present within the melted region, the Mcm helicase is mobilized and initiation takes place. A crucial question is how these double hexameric helicase complexes are generated and turn into active helicases at the origins. This process would involve melting of duplex DNA, which may be facilitated by binding of preRC components in the context of proper chromatin structures, or by other unwinding factors including a topoisomerase or a newly identified Mcm8 helicase (34–36). It may also require association of fork-assisting proteins such as Cdc45 (37,38) as well as phosphorylation events by Cdk and Cdc7 kinases (39,40). One unexpected finding of this study is low helicase activity of Mcm4/6/7 on GC-rich duplex DNA. This, in conjunction with the low processivity of Mcm4/6/7 helicase, strongly indicates that the replicative helicase at the replication forks would require more than Mcm4/6/7 complex. During the processive unwinding of duplex DNA replication forks, Mcm4/6/7 may be further stimulated by interaction with other proteins, including remaining Mcm subunits, Cdc45 (37,38), GINS (41,42), DNA polymerase subunits (43), Mcm8 (35,36), etc. to become a truly processive and potent helicase capable of replicating the entire genome."}

{"project":"2_test","denotations":[{"id":"15917436-9765408-76775546","span":{"begin":538,"end":540},"obj":"9765408"},{"id":"15917436-14993926-76775547","span":{"begin":1107,"end":1109},"obj":"14993926"},{"id":"15917436-15707891-76775547","span":{"begin":1107,"end":1109},"obj":"15707891"},{"id":"15917436-15684404-76775547","span":{"begin":1107,"end":1109},"obj":"15684404"},{"id":"15917436-9001208-76775548","span":{"begin":1189,"end":1191},"obj":"9001208"},{"id":"15917436-12581157-76775549","span":{"begin":1192,"end":1194},"obj":"12581157"},{"id":"15917436-10748114-76775550","span":{"begin":1255,"end":1257},"obj":"10748114"},{"id":"15917436-10846177-76775551","span":{"begin":1258,"end":1260},"obj":"10846177"},{"id":"15917436-9001208-76775552","span":{"begin":1722,"end":1724},"obj":"9001208"},{"id":"15917436-12581157-76775553","span":{"begin":1725,"end":1727},"obj":"12581157"},{"id":"15917436-12730134-76775554","span":{"begin":1736,"end":1738},"obj":"12730134"},{"id":"15917436-12730133-76775555","span":{"begin":1739,"end":1741},"obj":"12730133"},{"id":"15917436-11804324-76775556","span":{"begin":1769,"end":1771},"obj":"11804324"},{"id":"15917436-15707891-76775557","span":{"begin":1780,"end":1782},"obj":"15707891"},{"id":"15917436-15684404-76775558","span":{"begin":1783,"end":1785},"obj":"15684404"}],"text":"The results described in this manuscript reveal potentially important features of mammalian Mcm4/6/7 helicase, which is likely to be a key component of the eukaryotic replicative helicase. Prior to initiation of DNA replication, Mcm helicase may adopt a double hexameric complex at the partially melted origin region, and may catalyze concurrent unwinding of duplex DNA into both directions, while stably associated with the origins of DNA replication. This is similar to the T-antigen model originally proposed by Smelkova and Borowiec (21). We propose that, only when both hexamers are activated by the interacting thymine-rich sequences present within the melted region, the Mcm helicase is mobilized and initiation takes place. A crucial question is how these double hexameric helicase complexes are generated and turn into active helicases at the origins. This process would involve melting of duplex DNA, which may be facilitated by binding of preRC components in the context of proper chromatin structures, or by other unwinding factors including a topoisomerase or a newly identified Mcm8 helicase (34–36). It may also require association of fork-assisting proteins such as Cdc45 (37,38) as well as phosphorylation events by Cdk and Cdc7 kinases (39,40). One unexpected finding of this study is low helicase activity of Mcm4/6/7 on GC-rich duplex DNA. This, in conjunction with the low processivity of Mcm4/6/7 helicase, strongly indicates that the replicative helicase at the replication forks would require more than Mcm4/6/7 complex. During the processive unwinding of duplex DNA replication forks, Mcm4/6/7 may be further stimulated by interaction with other proteins, including remaining Mcm subunits, Cdc45 (37,38), GINS (41,42), DNA polymerase subunits (43), Mcm8 (35,36), etc. to become a truly processive and potent helicase capable of replicating the entire genome."}