Uracil and A Repair Pathway

An EMBO report entitled 'Abrogation of the CLK-2 checkpoint leads to tolerance to base-excision repair intermediates' focuses attention on another DNA damage response pathway. Misincorporated uracil leads to the necessity of a repair mechanism. The variety and extent of errors and damage causing malfunction in the absence of repair mechanisms highlights the need for repair mechanisms at a very early point in the history of life. From the EMBO report:


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.