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 repres-

sion

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

Fig 1 The phosphatase responsible for H3-pThr11 dephosphoryl-taion is sensitive to okadaic acid.

RESULTDephosphorylation 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

RESULTPP1γ is a H3-pThr 11 phosphatase

Fig 2 Protein phosphatase 1γ is responsible for DNA-damage-induced dephosphorylation of H3-pThr11.

RESULTRegulation of PP1γ activity in response to DNA damage

Fig 3 Protein phosphatase 1γ-pThr311 on chromatin is decreased after DNA damage.

RESULTATR–Chk1 axis regulates PP1γ activity

Fig 4 Cdk-dependent phosphorylation of protein phosphatase 1γ at Thr311 is in-volved in DNA-damage-induced transcriptional repression.

Caffeine : an inhibitor of ATR and ATM

Pur A (purvalanol A) : a specific Cdk inhibitor

Cdk1AF : constitutively active Cdk1 mutant

DISCUSSION

Fig 5 Schematic model of DNA-damage-induced dephosphory-lation of H3-pThr11 on the promoters of cell cycle regulatory genes.

DNA damage ↓ATR activation ↓Chk1 phosphorylation ↓Cdk activity suppression ↓Reduction in PP1γ-Thr311 phosphory-lation ↓PP1γ activation ↓H3-pThr11 dephosphorylation ↓Transcription repression ↓Cell cycle arrested