The chromosomes within eukaryotic cells experience many types of damage that are generated naturally via endogenous processes. The specific pathways that are most critical for repair of such endogenously produced DNA lesions have not been identified. Previous work revealed that budding yeast mutants deficient in double-strand break repair exhibit a persistent DNA damage checkpoint response leading to chronically high levels of G₂ phase cells, even in the absence of exogenous damaging agents. In the current study yeast mutants deficient in each of the five major DNA repair pathways were tested separately for the high G₂ cell phenotype. Cells with reduced homologous recombination (HR) and base excision repair (BER), but not nucleotide excision repair, mismatch repair or nonhomologous end-joining, displayed high levels of large-budded G₂ cells. BER mutants exhibiting this phenotype included apn1, apn2, ogg1, ung1, ntg1 and ntg2 cells. The persistent stress response was abolished by inactivation of the checkpoint gene RAD9. Cell cycling aberrations were increased synergistically in severely BER-deficient apn1 apn2 double mutants and strongly elevated in cells deficient in both HR and BER. apn1 apn2 rad52 cells were inviable but could be partially rescued by inactivation of UNG1. Transcription of the damage-inducible RNR3 (DIN1) gene was persistently activated in both BER and HR mutants. Like HR mutants, BER-deficient cells were larger in size and spent approximately three times longer in G₂ phase than wildtype cells. The results demonstrate that two pathways, HR and BER, are essential for repair of endogenously generated DNA lesions and prevention of a chronic cellular stress response.

• PMID: 41411878
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Journal Article

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Nepal Y, Ahmed S, Berry AM, Mahmood A, Holland CL, Lewis LK

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