Abstract
The roles of nucleotide excision repair (NER) proteins in removing UV-induced lesions are well defined. There are two distinct NER pathways: global genome NER (GG-NER) and transcriptioncoupled NER. In human GG-NER, two heteromeric protein complexes, DDB1-DDB2 and XPC-RAD23, are responsible for initial lesion recognition. Here, we examined the genetic interactions between GG-NER and base excision repair (BER) genes during abasic (AP) site repair of ＂Schizosaccharomyces pombe＂. Mutants of ＂rhp＂7 (＂rhp＂7-＂rhp＂16 are functional homologs of DDB1-DDB2) and ＂rhp＂41 (XPC homolog) were moderately sensitive to methyl methanesulfonate and slightly to sodium bisulfite. Nth1p most actively cleaves the AP site in ＂S. pombe＂. Deletion of ＂rhp＂7 or ＂rhp＂41 from ＂nth＂1Δ cells greatly increased their sensitivity to alkylation and deamination, indicating that Rhp7p and Rhp41p are involved in repair of the AP sites generated by the action of DNA glycosylase. Induction of ＂rhp＂7 and ＂rhp＂16 genes by different types of DNA damage supports the ability of GG-NER to remove non-bulky lesions. Therefore, GG-NER activity not only targets bulky DNA helix-distorting lesions, but can also efficiently remove AP sites synergistically with BER.
Highlights
Abasic (AP) sites are one of the most common DNA lesions and can be generated by the spontaneous hydrolysis of the sugar base glycosidic linkage or by the action of monofunctional DNA glycosylases, removing damaged bases formed by deamination, oxidation and alkylation
methyl methanesulfonate (MMS) damage is mainly repaired via the base excision repair (BER) pathway in many organisms, several S. pombe nucleotide excision repair (NER) mutants, including rad16∆ and rhp41∆, have been shown to display hypersensitivity to MMS [26] [30] [31]. rhp7∆ was sensitive to chronic exposure to MMS, indicating the contribution of Rhp7p to repair MMS-induced damage. rhp41∆ exhibited similar MMS sensitivity to rad16∆, and rhp7∆ was more weakly sensitive to MMS
These results suggest that global genome NER (GG-NER) proteins Rhp7p and Rhp41p are responsible, to different degrees, for the correction of MMS-induced DNA lesions
Summary
Abasic (AP) sites are one of the most common DNA lesions and can be generated by the spontaneous hydrolysis of the sugar base glycosidic linkage or by the action of monofunctional DNA glycosylases, removing damaged bases formed by deamination, oxidation and alkylation (reviewed in reference [1]). Base excision repair (BER) is the major pathway for the repair of AP sites, and is initiated by cleavage of the phosphodiester bond either by AP endonuclease or the AP lyase activity of bifunctional DNA glycosylase [5] [6]. AP lyase cleaves 3’ to the AP site leaving a 3’-α, β-unsaturated aldehyde (3’ block) and a 5’-phosphate. Following incision of the DNA backbone, 5’- or 3’-blocked ends are removed to allow repair DNA synthesis and ligation of the remaining nick. AP sites are incised mainly by AP lyase activity of Nth1p, a sole bifunctional glycosylase in the yeast, and the major AP endonuclease Apn2p functions predominantly in removing the 3’ block (Nth1p-dependent BER) [7][9]
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