Journal Article

ATM, ATR and DNA-PK: initiators of the cellular genotoxic stress responses

Jun Yang, Yingnian Yu, Hope E. Hamrick and Penelope J. Duerksen-Hughes

in Carcinogenesis

Volume 24, issue 10, pages 1571-1580
Published in print October 2003 | ISSN: 0143-3334
Published online October 2003 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgg137
ATM, ATR and DNA-PK: initiators of the cellular genotoxic stress responses

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Exposure to genotoxic agents is a major cause of human cancer, and cellular responses to genotoxic stress are important defense mechanisms. These responses are very complex, involving many cellular factors that form an extensive signal transduction network. This network includes a protein kinase cascade that connects the detection of DNA damage to the activation of transcription factors, which in turn regulate the expression of genes involved in DNA repair, cell cycle arrest and programmed cell death (apoptosis). The mitogen-activated protein kinases are the best-studied members of the kinase cascade with an acknowledged role in the genotoxic stress response. However, the initial activation of the protein kinase cascade is not fully understood, although several protein kinases, such as ataxia telangiectasia, mutated (ATM), ATM- and Rad3-related (ATR), and DNA-dependent protein kinase (DNA-PK) in humans, are increasingly recognized for their potential roles in the sensing of DNA damage and initiating the subsequent protein kinase cascade. In this review, the properties of these three kinases are discussed and their functions in the initiation of the genotoxic stress response are explored.

Keywords: ATM, ataxia telangiectasia, mutated; ATR, ATM- and Rad3-related; ATRIP, ATR-interacting protein; BRCA-1 breast cancer susceptibility gene 1; BRCT, BRCA-1 C-terminus; CPT, camptothecin; DNA-PK, DNA-dependent protein kinase; DSBs, double-strand breaks; FANCD2, Fanconi anaemia subtype D2 protein; FHA, forkhead-associated; γ-H2AX, phosphorylated H2AX; HDAC, histone deacetylase; HR, homologous recombination; IR, ionizing irradiation; JNK/SAPK, c-Jun N-terminal kinase/stress-activated protein kinase; MAPKs, mitogen-activated protein kinases; MDC1, mediator of DNA damage checkpoint protein 1; NHEJ, non-homologous end-joining; PCNA, proliferating cell nuclear antigen; PI-3, phosphatidylinositol 3-kinase; PML, promyelocytic leukemia protein; PP1, protein phosphatase 1; RB, retinoblastoma protein; RPA, replication protein A; SAPK, stress-activated protein kinase; ssDNA, single-stranded DNA; TopBP1, DNA topoisomerase IIβ binding protein 1; WRN, Werner's syndrome protein

Journal Article.  8928 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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