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Physical and functional interactions between nucleotide excision repair and DNA damage checkpoint
Author(s) -
Giannattasio Michele,
Lazzaro Federico,
Longhese Maria Pia,
Plevani Paolo,
MuziFalconi Marco
Publication year - 2004
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600051
Subject(s) - biology , g2 m dna damage checkpoint , nucleotide excision repair , dna repair , dna damage , chek1 , microbiology and biotechnology , genetics , dna binding protein , dna , gene , cell cycle checkpoint , transcription factor , cell cycle
The mechanisms used by checkpoints to identify DNA lesions are poorly understood and may involve the function of repair proteins. Looking for mutants specifically defective in activating the checkpoint following UV lesions, but proficient in the response to methyl methane sulfonate and double‐strand breaks, we isolated cdu1‐1 , which is allelic to RAD14 , the homolog of human XPA, involved in lesion recognition during nucleotide excision repair (NER). Rad14 was also isolated as a partner of the Ddc1 checkpoint protein in a two‐hybrid screening, and physical interaction was proven by co‐immunoprecipitation. We show that lesion recognition is not sufficient for checkpoint activation, but processing, carried out by repair factors, is required for recruiting checkpoint proteins to damaged DNA. Mutations affecting the core NER machinery abolish G1 and G2 checkpoint responses to UV, preventing activation of the Mec1 kinase and its binding to chromosomes. Conversely, elimination of transcription‐coupled or global genome repair alone does not affect checkpoints, suggesting a possible interpretation for the heterogeneity in cancer susceptibility observed in different NER syndrome patients.