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J. Biol. Chem., Vol. 279, Issue 29, 30228-30235, July 16, 2004

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Interaction of Nick-directed DNA Mismatch Repair and Loop Repair in Human Cells^*

Yao-Ming Huang, Shee-Uan Chen, Steven D. Goodman¶, Shang-Hsin Wu, Jau-Tsuen Kao||, Chun-Nan Lee||, Wern-Cherng Cheng||, Keh-Sung Tsai||, and Woei-horng Fang||**

From the School of Medical Technology and the Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, and the ^||Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan 100-63, Republic of China and the ^¶Division of Diagnostic Sciences, University of Southern California School of Dentistry, Los Angeles, California 90089-0641

In human cells, large DNA loop heterologies are repaired through a nick-directed pathway independent of mismatch repair. However, a 3'-nick generated by bacteriophage fd gene II protein heterology is not capable of stimulating loop repair. To evaluate the possibility that a mismatch near a loop could induce both repair types in human cell extracts, we constructed and tested a set of DNA heteroduplexes, each of which contains a combination of mismatches and loops. We have demonstrated that a strand break generated by restriction endonucleases 3' to a large loop is capable of provoking and directing loop repair. The repair of 3'-heteroduplexes in human cell extracts is very similar to that of 5'-heteroduplex repair, being strand-specific and highly biased to the nicked strand. This observation suggests that the loop repair pathway possesses bidirectional repair capability similar to that of the bacterial loop repair system. We also found that a nick 5' to a coincident mismatch and loop can apparently stimulate the repair of both. In contrast, 3'-nick-directed repair of a G-G mismatch was reduced when in the vicinity of a loop (33 or 46 bp between two sites). Increasing the distance separating the G-G mismatch and loop by 325 bp restored the efficiency of repair to the level of a single base-base mismatch. This observation suggests interference between 3'-nick-directed large loop repair and conventional mismatch repair systems when a mispair is near a loop. We propose a model in which DNA repair systems avoid simultaneous repair at adjacent sites to avoid the creation of double-stranded DNA breaks.

Received for publication, February 16, 2004 , and in revised form, March 25, 2004.

^* This work was supported by Grants NSC91-2314-B-002-243 (to W.-h. F.) and NSC88-2314-B-002-092-M40 (to J.-T. K.) from the National Science Council (Taipei, Taiwan, Republic of China). 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.

^** To whom correspondence should be addressed: School of Medical Technology, College of Medicine, National Taiwan University, 7 Chung-Shan South Rd., Taipei, Taiwan 100-63, Republic of China. Tel.: 886-2-2312-3456 (ext. 6926); Fax: 886-2-2371-1574; E-mail: whfang{at}ha.mc.ntu.edu.tw.

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