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Abrogation of the CLK‐2 checkpoint leads to tolerance to base‐excision repair intermediates
Author(s) -
Dengg Marlene,
GarciaMuse Tatiana,
Gill Stephen G,
Ashcroft Neville,
Boulton Simon J,
Nilsen Hilde
Publication year - 2006
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.1038/sj.embor.7400782
Subject(s) - uracil , dna repair , g2 m dna damage checkpoint , dna damage , uracil dna glycosylase , dna glycosylase , biology , cell cycle checkpoint , microbiology and biotechnology , dna , synthetic lethality , base excision repair , chek1 , cell cycle , genetics , chemistry , apoptosis
Incorporation of uracil during DNA synthesis is among the most common types of endogenously generated DNA damage. Depletion of Caenorhabditis elegans dUTPase by RNA interference allowed us to study the role of DNA damage response (DDR) pathways when responding to high levels of uracil in DNA. dUTPase depletion compromised development, caused embryonic lethality and led to activation of cell‐cycle arrest and apoptosis. These phenotypes manifested as a result of processing misincorporated uracil by the uracil‐DNA glycosylase UNG‐1. Strikingly, abrogation of the clk‐2 checkpoint gene rescued lethality and developmental defects, and eliminated cell‐cycle arrest and apoptosis after dUTPase depletion. These data show a genetic interaction between UNG‐1 and activation of the CLK‐2 DDR pathway after uracil incorporation into DNA. Our results indicate that persistent repair intermediates and/or single‐stranded DNA formed during repair of misincorporated uracil are tolerated in the absence of the CLK‐2 checkpoint in C. elegans .