Protein kinases that regulate chromosome stability and their downstream targets

Genome Dynamics
H Nojima

Abstract

Upon genotoxic stress, checkpoint machinery in eukaryotic cells induces cell-cycle arrest, thus allowing the cells to repair damaged DNA or stalled replication forks. The checkpoint machinery is mediated by phosphorylation cascades involving protein kinases and their target proteins. Since the genome is under constant threat from DNA damage due to radiation, chemicals and replication errors, checkpoint dysregulation can cause catastrophic DNA damage, resulting in chromosome instability, aneuploidy, and even tumorigenesis. Two parallel pathways that respond to DNA-damage stress have been extensively studied. The first is the ATM pathway, which responds to double-stranded DNA breaks, while the second is the ATR pathway, which primarily responds to agents that interfere with normal DNA replication. The ATM and ATR kinases activate their downstream target proteins by phosphorylating specific serine or threonine residues. Dephosphorylation by protein phosphatase (PP2A) also participates in the regulation of these phosphorylation signals. Of the target proteins, the two effector kinases CHK1 and CHK2 are particularly important because they phosphorylate additional substrates to maintain chromosome stability after various DNA damaging...Continue Reading

Citations

Mar 6, 2012·The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences·Andrew T LudlowStephen M Roth
Aug 19, 2011·Clinical Oral Investigations·Shuei-Kuen TsengJiiang-Huei Jeng
Oct 26, 2010·Current Biology : CB·Aimee Jaramillo-LambertJoAnne Engebrecht

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