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Title: The Rad9.M50 variant of the DNA damage checkpoint protein Rad9 regulates the MAP kinase pathway in the response to heat stress
Author: Oun, Rabiaa R. Salah
ISNI:       0000 0004 6057 1497
Awarding Body: Prifysgol Bangor University
Current Institution: Bangor University
Date of Award: 2016
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Environmental stress activates the MAP kinase pathway to regulate transcription and cell division. In this pathway, a MAP kinase kinase kinases (MAPKKK) activates the MAP kinase kinase (MAPKK) which in turn phosphorylates the MAP kinase (MAPK) simultaneously at a serine or threonine residue and a tyrosine residue in close vicinity. In the fission yeast Schizosaccharomyces pombe, the dual specific MAPKK Wis1 phosphorylates the MAPK Sty1/Spc1 at threonine 171 and tyrosine 173. Active Sty1 phosphorylates and activates the transcription factor Atf1. Sty1 is closely related to Hog1 in the budding yeast S.cerevisiae and p38 in human cells. This thesis reveals a novel regulation of Sty1 by the alternative translation product of the DNA damage checkpoint protein Rad9. Alternative translation from the internal AUG codon at position 50 produces an N-terminally truncated protein variant (Rad9-M50), expression of which is restricted to dividing cells. The basal level of this variant is low and increases in the response to heat stress and DNA alkylation by the DNA damaging drug methyl-methanesulfonate (MMS). The key finding reported here is the ability of Rad9 variant to shield Sty1 from dual specific kinases other than Wis1. Loss of Wis1 eliminates the phosphorylation of Sty1 at T171 and Y173. However, removal of the Rad9 variant (rad9-M50A) restores Sty1 phosphorylation in the absence of Wis1 at high temperature and in the presence of oxidative stress. This aberrant stimulation enables Sty1 to phosphorylate Atf1. A model is presented in which Rad9 variant shields Sty1 from an alternative dual-specific kinase, possibly Wee1, Hhp1 (CK1) or Mps1/TTK. The thesis also reports the requirement of the DEAD-box RNA helicase Ded1 for the expression of Rad9 variant and presents genetic evidence linking Rad9 variant with the phosphatase Ptc1 in the response to heat stress and MMS induced DNA damage.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available