Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P21817 (RyR1)
 1,154 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cellular response to the introduction of double strand DNA breaks involves complexes of protein interactions that govern cell cycle checkpoint arrest and repair of the DNA lesions. The checkpoint kinases Chk1 and Chk2 phosphorylate the carboxy-terminal domain of hBRCA2, a protein involved in recombination-mediated DNA repair (HRR) and replication fork maintenance. Cells deficient in hBRCA2 are hypersensitive to DNA damaging agents. Phosphorylation of the residue in hBRCA2 targeted by the Chk1 and Chk2 kinases regulates its interaction with Rad51. Furthermore, the cell line lex1/lex2, which lacks the carboxy-terminal domain containing the phosphorylated residue, does not support localization of Rad51 to nuclear foci after exposure to UV or treatment with ionizing radiation (IR). The data show that either phosphorylation of Rad51 by Chk1 or phosphorylation of the carboxy-terminal domain of hBRCA2 by Chk1 or Chk2 plays a critical role in the binding of Rad51 to hBRCA2 and the subsequent recruitment of Rad51 to sites of DNA damage. While depletion of Chk1 from cells leads to loss of Rad51 localization to nuclear foci in response to replication arrest, cells lacking Chk2 also show a defect in Rad51 localization, but only in presence of double strand DNA breaks, indicating that each of these kinases may contribute somewhat differently to the formation of Rad51 nucleoprotein filaments depending on the type of DNA damage incurred by the cells.
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PMID:The checkpoint kinases Chk1 and Chk2 regulate the functional associations between hBRCA2 and Rad51 in response to DNA damage. 1831 53

DNA damage is a key factor both in the evolution and treatment of cancer. Genomic instability is a common feature of cancer cells, fuelling accumulation of oncogenic mutations, while radiation and diverse genotoxic agents remain important, if imperfect, therapeutic modalities. Cellular responses to DNA damage are coordinated primarily by two distinct kinase signaling cascades, the ATM-Chk2 and ATR-Chk1 pathways, which are activated by DNA double-strand breaks (DSBs) and single-stranded DNA respectively. Historically, these pathways were thought to act in parallel with overlapping functions; however, more recently it has become apparent that their relationship is more complex. In response to DSBs, ATM is required both for ATR-Chk1 activation and to initiate DNA repair via homologous recombination (HRR) by promoting formation of single-stranded DNA at sites of damage through nucleolytic resection. Interestingly, cells and organisms survive with mutations in ATM or other components required for HRR, such as BRCA1 and BRCA2, but at the cost of genomic instability and cancer predisposition. By contrast, the ATR-Chk1 pathway is the principal direct effector of the DNA damage and replication checkpoints and, as such, is essential for the survival of many, although not all, cell types. Remarkably, deficiency for HRR in BRCA1- and BRCA2-deficient tumors confers sensitivity to cisplatin and inhibitors of poly(ADP-ribose) polymerase (PARP), an enzyme required for repair of endogenous DNA damage. In addition, suppressing DNA damage and replication checkpoint responses by inhibiting Chk1 can enhance tumor cell killing by diverse genotoxic agents. Here, we review current understanding of the organization and functions of the ATM-Chk2 and ATR-Chk1 pathways and the prospects for targeting DNA damage signaling processes for therapeutic purposes.
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PMID:The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer. 2103 66