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The DNA Damage Response Induces Autophagy via Mec1(ATR) and Tel1(ATM) to Regulate the Initiation of Anaphase
Author(s) -
Eapen Vinay,
Waterman David,
Bernard Amelie,
Ang Jessie,
Klionsky Daniel,
Haber James
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.879.16
Subject(s) - dna damage , g2 m dna damage checkpoint , microbiology and biotechnology , autophagy , chek1 , biology , checkpoint kinase 2 , anaphase , mitosis , dna repair , cell cycle checkpoint , chemistry , dna , cell cycle , kinase , protein kinase a , genetics , cell , apoptosis , protein serine threonine kinases
Eukaryotic cells respond to DNA damage by activating the DNA damage checkpoint, which serves to delay the onset of anaphase in order to allow enough time for the repair of DNA lesions. In eukaryotes, the checkpoint signaling cascade is controlled by the highly conserved kinases Mec1 (ATR) and Tel1 (ATM). The mechanism by which the checkpoint is initiated has been well studied but it is not well understood how such signals are turned off to allow mitotic progression. Using budding yeast ,we have isolated mutants that are unable to resume mitosis after DNA damage. We showed that mutations that hyperactivate the cellular degradation pathway of autophagy prevented mitosis after DNA damage due to the degradation of mitotic regulators such as Securin(Pds1), however, it was not known if the DNA damage response could itself induce autophagy. We now show for the first time that DNA damage checkpoint induces autophagy in budding yeast in a Mec1/Rad53(Chk2) dependent manner. Autophagy induction after damage occurs via a two‐pronged mechanism: 1) Rad53 dependent transcriptional upregulation of various autophagy related genes mediated by the transcriptional repressor Rph1 and 2) post‐translational modifications on autophagy related proteins. We also demonstrate that defined DNA damage, such as a single DNA double strand break cause by the HO endonuclease can also induce autophagy and that this phenomenon is sensitive to the amount of DNA damage that is inflicted. Finally we show that autophagy mutants have a reduced duration of checkpoint arrest thereby supporting an overall model in which DNA damage induction of autophagy serves to regulate the onset of anaphase.