Open AccessGenetic Instability Induced by Overexpression of DNA Ligase I in Budding Yeast
Author(s) -
Jaichandar Subramanian,
Sangeetha Vijayakumar,
Alan E. Tomkinson,
Norman Arnheim
Publication year - 2005
Publication title -
genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.792
H-Index - 246
eISSN - 1943-2631
pISSN - 0016-6731
DOI - 10.1534/genetics.105.042861
Subject(s) - biology , dna ligase , mitotic crossover , dna replication , genetics , trinucleotide repeat expansion , dna repair , dna mismatch repair , okazaki fragments , proliferating cell nuclear antigen , genome instability , dna , microbiology and biotechnology , homologous recombination , dna damage , eukaryotic dna replication , gene , allele
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.
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