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Molecular and Cellular Biology, February 2006, p. 1424-1433, Vol. 26, No. 4
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.4.1424-1433.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Regulation of Gross Chromosomal Rearrangements by Ubiquitin and SUMO Ligases in Saccharomyces cerevisiae

Akira Motegi, Karen Kuntz,{dagger} Anju Majeed, Stephanie Smith, and Kyungjae Myung*

Genome Instability Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, 49 Convent Drive, Bethesda, Maryland 20892

Received 10 August 2005/ Returned for modification 21 September 2005/ Accepted 18 November 2005

Gross chromosomal rearrangements (GCRs) are frequently observed in many cancers. Previously, we showed that inactivation of Rad5 or Rad18, ubiquitin ligases (E3) targeting for proliferating cell nuclear antigen (PCNA), increases the de novo telomere addition type of GCR (S. Smith, J. Y. Hwang, S. Banerjee, A. Majeed, A. Gupta, and K. Myung, Proc. Natl. Acad. Sci. USA 101:9039-9044, 2004). GCR suppression by Rad5 and Rad18 appears to be exerted by the RAD5-dependent error-free mode of bypass DNA repair. In contrast, Siz1 SUMO ligase and another ubiquitin ligase, Bre1, which target for PCNA and histone H2B, respectively, have GCR-supporting activities. Inactivation of homologous recombination (HR) proteins or the helicase Srs2 reduces GCR rates elevated by the rad5 or rad18 mutation. GCRs are therefore likely to be produced through the restrained recruitment of an HR pathway to stalled DNA replication forks. Since this HR pathway is compatible with Srs2, it is not a conventional form of recombinational pathway. Lastly, we demonstrate that selection of proper DNA repair pathways to stalled DNA replication forks is controlled by the Mec1-dependent checkpoint and is executed by cooperative functions of Siz1 and Srs2. We propose a mechanism for how defects in these proteins could lead to diverse outcomes (proper repair or GCR formation) through different regulation of DNA repair machinery.

* Corresponding author. Mailing address: Genome Instability Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Building 49, Room 4A22, Bethesda, MD 20892. Phone: (301) 451-8748. Fax: (301) 402-4929. E-mail: kmyung{at}nhgri.nih.gov.

{dagger} Present address: Cold Spring Harbor Laboratory, 1 Bungtown Rd., Cold Spring Harbor, NY 11724.

Molecular and Cellular Biology, February 2006, p. 1424-1433, Vol. 26, No. 4
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.4.1424-1433.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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