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Protein phosphatase 1γ is responsible for
dephosphorylation of histone H3 at Thr 11
after DNA damage
INTRODUCTION
Systems to respond to DNA damage
- cell cycle arrest mechanism
- DNA repair pathways
- apoptotic response
>> partly regulated by transcriptional activation and repression
Histone H3-Thr 11 phosphorylation
- new transcriptional marker
- rapidly decreases after DNA damage
- phosphorylated by Chk1
Mammalian Ser/Thr-specific protein phosphatases
- 8 prototypes : PP1, PP2A, PP2B, PP2C, PP4, PP5, PP6 and PP7
⇒Histone phosphatase
RESULT
Dephosphorylation of pThr 11 is okadaic acid sensitive
OA (okadaic acid)
: PP1, 2A and 2B inhibitor
MI (mitotic index)
: the percentage of cells with
condensed chromosomes
RO3306
: inhibits Cdk1 and
prevents mitotic entry
Fostriecin
: a specific inhibitor of PP2A
and PP4, 6 isotypes
Fig 1 The phosphatase responsible for H3-pThr11 dephosphoryltaion is
sensitive to okadaic acid.
RESULT
PP1γ is a H3-pThr 11 phosphatase
Fig 2 Protein phosphatase 1γ is responsible for DNA-damage-induced dephosphorylation of H3-pThr11.
RESULT
Regulation of PP1γ activity in response to DNA damage
Fig 3 Protein phosphatase 1γ-pThr311 on chromatin is decreased after DNA damage.
RESULT
ATR–Chk1 axis regulates PP1γ activity
Caffeine
: an inhibitor of ATR and ATM
Pur A (purvalanol A)
: a specific Cdk inhibitor
Cdk1AF
: constitutively active
Cdk1 mutant
Fig 4 Cdk-dependent phosphorylation of protein phosphatase 1γ at Thr311 is involved
in DNA-damage-induced transcriptional repression.
DISCUSSION
DNA damage
↓
ATR activation
↓
Chk1 phosphorylation
↓
Cdk activity suppression
↓
Reduction in PP1γ-Thr311 phosphorylation
↓
PP1γ activation
↓
H3-pThr11 dephosphorylation
↓
Transcription repression
↓
Cell cycle arrested
Fig 5 Schematic model of DNA-damage-induced dephosphorylation
of H3-pThr11 on the promoters of cell cycle regulatory genes.