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J. Biol. Chem., Vol. 283, Issue 30, 20925-20936, July 25, 2008

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Studies with the Human Cohesin Establishment Factor, ChlR1

ASSOCIATION OF ChlR1 WITH Ctf18-RFC AND Fen1^*

Andrea Farina, Jae-Ho Shin, Do-Hyung Kim^¶, Vladimir P. Bermudez, Zvi Kelman, Yeon-Soo Seo^¶1, and Jerard Hurwitz²

From the Program of Molecular Biology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, the University of Maryland Biotechnology Institute, Rockville, Maryland 20850, and the ^¶Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, 305-701, Korea

Human ChlR1 (hChlR1), a member of the DEAD/DEAH subfamily of helicases, was shown to interact with components of the cohesin complex and play a role in sister chromatid cohesion. In order to study the biochemical and biological properties of hChlR1, we purified the protein from 293 cells and demonstrated that hChlR1 possesses DNA-dependent ATPase and helicase activities. This helicase translocates on single-stranded DNA in the 5' to 3' direction in the presence of ATP and, to a lesser extent, dATP. Its unwinding activity requires a 5'-singlestranded region for helicase loading, since flush-ended duplex structures do not support unwinding. The helicase activity of hChlR1 is capable of displacing duplex regions up to 100 bp, which can be extended to 500 bp by RPA or the cohesion establishment factor, the Ctf18-RFC (replication factor C) complex. We show that hChlR1 interacts with the hCtf18-RFC complex, human proliferating cell nuclear antigen, and hFen1. The interactions between Fen1 and hChlR1 stimulate the flap endonuclease activity of Fen1. Selective depletion of either hChlR1 or Fen1 by targeted small interfering RNA treatment results in the precocious separation of sister chromatids. These findings are consistent with a role of hChlR1 in the establishment of sister chromatid cohesion and suggest that its action may contribute to lagging strand processing events important in cohesion.

Received for publication, April 8, 2008 , and in revised form, May 21, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants GM 34559 and GM 27440 (to J. H.). This work was also supported by American Cancer Society Research Scholar Grant RSG-04-050-01-GMC (to Z. K.). 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.

¹ Present address: School of Applied Biosciences, Kyungpook National University, Daegu 702-701, Republic of Korea.

² To whom correspondence should be addressed: 1275 York Ave., Box 97, New York, NY 10065. Tel.: 212-639-5896; Fax: 212-717-3627; E-mail: j-hurwitz{at}ski.mskcc.org.

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