Lack of Bcl11b tumor suppressor results in vulnerability to DNA replication stress and damages.
Bcl11b/Rit1 is involved in T-cell development and undergoes chromosomal rearrangements in human T-cell leukemias. Thymocytes of Bcl11b(-/-) newborn mice exhibit apoptosis at a certain developmental stage when thymocytes re-enter into the cell-cycle. Here, we show that Bcl11b-knockdown T-cell lines, when exposed to growth stimuli, exhibited apoptosis at the S phase with concomitant decreases in a cell-cycle inhibitor, p27 and an antiapoptotic protein, Bcl-xL, owing to transcriptional repression. This repression was a likely consequence of the impairment of Sirt1, a nicotinamide adenine dinucleotide-dependent deacetylase associating with Bcl11b. Activation of the apoptotic process cleaved the mediator protein, Claspin, and inhibited phosphorylation of cell-cycle checkpoint kinase 1 (Chk1) that plays a central role in sensing and responding to incomplete replication. Bcl11b(-/-) thymocytes also failed to phosphorylate Chk1 when UV irradiated. These results implicate Bcl11b in the remedy for DNA replication stress and maintenance of genomic integrity.
Kamimura
K
K
Department of Molecular Genetics, Niigata University Graduate School of Medical and Dental Sciences, Asahimachi 1-757, Niigata 951-8510, Japan.
Mishima
Y
Y
Obata
M
M
Endo
T
T
Aoyagi
Y
Y
Kominami
R
R
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D002453:Cell Cycle; D000071877:Checkpoint Kinase 1; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011494:Protein Kinases / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D056564:Sirtuin 1; D037761:Sirtuins / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*; D051020:bcl-X Protein / Q000378:metabolism
C479740:BCL11B protein, human; C511143:Bcl11b protein, mouse; D004268:DNA-Binding Proteins; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D051020:bcl-X Protein; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins