Phospho-Bcl-x(L)(Ser62) plays a key role at DNA damage-induced G(2) checkpoint.
CELL CYCLE(2012)
Abstract
Accumulating evidence suggests that Bcl-x(L), an anti-apoptotic member of the Bcl-2 family, also functions in cell cycle progression and cell cycle checkpoints. Analysis of a series of phosphorylation site mutants reveals that cells expressing Bcl-x(L) (Ser62Ala) mutant are less stable at the G(2) checkpoint and enter mitosis more rapidly than cells expressing wildtype Bcl-x(L) or Bcl-x(L) phosphorylation site mutants, including Thr41Ala, Ser43Ala, Thr47Ala, Ser56Ala and Thr115Ala. Analysis of the dynamic phosphorylation and location of phospho-Bcl-x(L)(Ser62) in unperturbed, synchronized cells and during DNA damage-induced G(2) arrest discloses that a pool of phospho-Bcl-x(L)(Ser62) accumulates into nucleolar structures in etoposide-exposed cells during G(2) arrest. In a series of in vitro kinase assays, pharmacological inhibitors and specific siRNAs experiments, we found that Polo kinase 1 and MAPK9/JNK2 are major protein kinases involved in Bclx(L)(Ser62) phosphorylation and accumulation into nucleolar structures during the G(2) checkpoint. In nucleoli, phospho-Bcl-x(L)(Ser62) binds to and co-localizes with Cdk1(cdc2), the key cyclin-dependent kinase required for entry into mitosis. These data indicate that during G(2) checkpoint, phospho-Bcl-x(L)(Ser62) stabilizes G(2) arrest by timely trapping of Cdk1(cdc2) in nucleolar structures to slow mitotic entry. It also highlights that DNA damage affects the dynamic composition of the nucleolus, which now emerges as a piece of the DNA damage response.
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Key words
Bcl-x(L),cdk1(cdc2),cell cycle checkpoint,DNA damage,nucleolus
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