THESIS
2015
iii leaves, iv-xii, 154 pages : illustrations (some color) ; 30 cm
Abstract
MASTL is the human orthologue of Greatwall kinase (Gwl), which is known to facilitate
mitotic entry by inhibiting PP2A via endosulfine (ENSA) and ARPP19. However, the full
functions of MASTL in other aspects of cell cycle control in mammalian cell still remained to
be deciphered. In this thesis, I study the involvement of MASTL in the G
2 DNA damage
checkpoint. After DNA is damaged, cells arrest at G
2 until the damaged DNA is repaired. I
found that MASTL did not conserve the mechanism of Greatwall kinase during nuclear
exclusion as it did not require the phosphorylation of PLK1 for the binding to 14-3-3, but it
conserved the function of Greatwall kinase during checkpoint recovery. MASTL did not take
part in checkpoint activation but controlled the timing of checkpoint recovery vi...[
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MASTL is the human orthologue of Greatwall kinase (Gwl), which is known to facilitate
mitotic entry by inhibiting PP2A via endosulfine (ENSA) and ARPP19. However, the full
functions of MASTL in other aspects of cell cycle control in mammalian cell still remained to
be deciphered. In this thesis, I study the involvement of MASTL in the G
2 DNA damage
checkpoint. After DNA is damaged, cells arrest at G
2 until the damaged DNA is repaired. I
found that MASTL did not conserve the mechanism of Greatwall kinase during nuclear
exclusion as it did not require the phosphorylation of PLK1 for the binding to 14-3-3, but it
conserved the function of Greatwall kinase during checkpoint recovery. MASTL did not take
part in checkpoint activation but controlled the timing of checkpoint recovery via PP2A
pathway. Depletion of MASTL delayed the recovery while expression of a hyperactive mutant
of MASTL promoted the recovery even in absence of PLK1 activity. Also, depletion of
MASTL induced premature activation of APC/C after DNA damage and leaded to the
subsequent DNA re-replication, which suggested MASTL was required to prevent
endo-replication after DNA damage. I also showed that the amount and activity of MASTL
have to be monitored precisely as either more or less would impede normal cell growth. These
data extended our understanding of MASTL during G
2 DNA damage checkpoint. Based on
these findings, I propose that MASTL regulates the G
2 DNA damage checkpoint and is crucial
for maintaining the genome stability after DNA damage.
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