| Title | A role for Chk1 in blocking transcriptional elongation of p21 RNA during the S-phase checkpoint. | | Author(s) | Beckerman R, Donner AJ, Mattia M, Peart MJ, Manley JL, Espinosa JM, Prives C | | Institution | Department of Biological Sciences, Columbia University, New York, New York 10027, USA. | | Source | Genes Dev 2009 Jun 1; 23(11):1364-77. | | MeSH | Caffeine
Cell Cycle Proteins
Cyclin-Dependent Kinase Inhibitor p21
DNA Replication
Daunorubicin
Gene Expression Regulation, Neoplastic
HCT116 Cells
Humans
Hydroxyurea
Nucleic Acid Synthesis Inhibitors
Promoter Regions, Genetic
Protein Kinases
Protein-Serine-Threonine Kinases
RNA, Messenger
S Phase
Signal Transduction
Transcription Factors
Tumor Suppressor Protein p53
| | Abstract | We reported previously that when cells are arrested in S phase, a subset of p53 target genes fails to be strongly induced despite the presence of high levels of p53. When DNA replication is inhibited, reduced p21 mRNA accumulation is correlated with a marked reduction in transcription elongation. Here we show that ablation of the protein kinase Chk1 rescues the p21 transcription elongation defect when cells are blocked in S phase, as measured by increases in both p21 mRNA levels and the presence of the elongating form of RNA polymerase II (RNAPII) toward the 3' end of the p21 gene. Recruitment of specific elongation and 3' processing factors (DSIF, CstF-64, and CPSF-100) is also restored. While additional components of the RNAPII transcriptional machinery, such as TFIIB and CDK7, are recruited more extensively to the p21 locus after DNA damage than after replication stress, their recruitment is not enhanced by ablation of Chk1. Significantly, ablating Chk2, a kinase closely related in substrate specificity to Chk1, does not rescue p21 mRNA levels during S-phase arrest. Thus, Chk1 has a direct and selective role in the elongation block to p21 observed during S-phase arrest. These findings demonstrate for the first time a link between the replication checkpoint mediated by ATR/Chk1 and the transcription elongation/3' processing machinery. | | Language | eng | | Pub Type(s) | Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
| | PubMed ID | 19487575 |
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