Originally published as Genetics Published Articles Ahead of Print on June 18, 2005.

Genetics, Vol. 171, 427-441, October 2005, Copyright © 2005
doi:10.1534/genetics.105.042861

Genetic Instability Induced by Overexpression of DNA Ligase I in Budding Yeast

Jaichandar Subramanian*, Sangeetha Vijayakumar{dagger}, Alan E. Tomkinson{ddagger} and Norman Arnheim*,1

* Molecular and Computational Biology Program, University of Southern California, Los Angeles, California 90089-2910, {dagger} Molecular and Cell Biology Graduate Program, University of Maryland Graduate School, Baltimore, Maryland 21201-1509 and {ddagger} Radiation Oncology Research Laboratory, Department of Radiation Oncology and Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201

1 Corresponding author: Molecular and Computational Biology Program, University of Southern California, 835 West 37th St., Los Angeles, CA 90089-1340.
E-mail: arnheim{at}usc.edu

Recombination and microsatellite mutation in humans contribute to disorders including cancer and trinucleotide repeat (TNR) disease. TNR expansions in wild-type yeast may arise by flap ligation during lagging-strand replication. Here we show that overexpression of DNA ligase I (CDC9) increases the rates of TNR expansion, of TNR contraction, and of mitotic recombination. Surprisingly, this effect is observed with catalytically inactive forms of Cdc9p protein, but only if they possess a functional PCNA-binding site. Furthermore, in vitro analysis indicates that the interaction of PCNA with Cdc9p and Rad27p (Fen1) is mutually exclusive. Together our genetic and biochemical analysis suggests that, although DNA ligase I seals DNA nicks during replication, repair, and recombination, higher than normal levels can yield genetic instability by disrupting the normal interplay of PCNA with other proteins such as Fen1.




This article has been cited by other articles:


Home page
 J. Biol. Chem.Home page
A. Lopez Castel, A. E. Tomkinson, and C. E. Pearson
CTG/CAG Repeat Instability Is Modulated by the Levels of Human DNA Ligase I and Its Interaction with Proliferating Cell Nuclear Antigen: A DISTINCTION BETWEEN REPLICATION AND SLIPPED-DNA REPAIR
J. Biol. Chem., September 25, 2009; 284(39): 26631 - 26645.
[Abstract] [Full Text] [PDF]

Home page
 Microbiol. Mol. Biol. Rev.Home page
G.-F. Richard, A. Kerrest, and B. Dujon
Comparative Genomics and Molecular Dynamics of DNA Repeats in Eukaryotes
Microbiol. Mol. Biol. Rev., December 1, 2008; 72(4): 686 - 727.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
L. Zheng, H. Dai, J. Qiu, Q. Huang, and B. Shen
Disruption of the FEN-1/PCNA Interaction Results in DNA Replication Defects, Pulmonary Hypoplasia, Pancytopenia, and Newborn Lethality in Mice
Mol. Cell. Biol., April 15, 2007; 27(8): 3176 - 3186.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
S. Vijayakumar, B. R. Chapados, K. H. Schmidt, R. D. Kolodner, J. A. Tainer, and A. E. Tomkinson
The C-terminal domain of yeast PCNA is required for physical and functional interactions with Cdc9 DNA ligase
Nucleic Acids Res., March 12, 2007; 35(5): 1624 - 1637.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
P. Singh, L. Zheng, V. Chavez, J. Qiu, and B. Shen
Concerted Action of Exonuclease and Gap-dependent Endonuclease Activities of FEN-1 Contributes to the Resolution of Triplet Repeat Sequences (CTG)n- and (GAA)n-derived Secondary Structures Formed during Maturation of Okazaki Fragments
J. Biol. Chem., February 9, 2007; 282(6): 3465 - 3477.
[Abstract] [Full Text] [PDF]