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J. Biol. Chem., Vol. 280, Issue 40, 34143-34151, October 7, 2005

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Unwinding of the Nascent Lagging Strand by Rep and PriA Enables the Direct Restart of Stalled Replication Forks^*

Ryan C. Heller and Kenneth J. Marians1

From the Programs in Molecular Biology, Weill Graduate School of Medical Sciences of Cornell University and Memorial Sloan-Kettering Cancer Center, New York, New York 10021

During origin-independent replisome assembly, the replication restart protein PriC prefers to load the replication fork helicase, DnaB, to stalled replication forks where there is a gap in the nascent leading strand. However, this activity can be obstructed if the 5'-end of the nascent lagging strand is near the template branch point. Here we provide biochemical evidence that the helicase activities of Rep and PriA function to unwind the nascent lagging strand DNA at such stalled replication forks. PriC then loads the replicative helicase, DnaB, onto the newly generated, single-stranded template for the purposes of replisome assembly and duplex unwinding ahead of the replication fork. Direct rescue of replication forks by the Rep-PriC and PriA-PriC pathways in this manner may contribute to genomic stability by avoiding the potential dangers of fork breakage inherent to recombination-dependent restart pathways.

Received for publication, July 5, 2005 , and in revised form, August 2, 2005.

^* These studies were supported by National Institutes of Health Grant GM34557. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence should be addressed: Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021. Tel.: 212-639-5890; Fax: 212-717-3627; E-mail: kmarians{at}sloankettering.edu.

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