Mechanisms of ATR-mediated checkpoint signalling

Abstract

Cell cycle checkpoints maintain genomic integrity by delaying cell division in the presence of DNA damage or replication problems. A crucial player in this process is the ATR kinase. The rapid localisation of ATR to sites of genotoxic stress and the central role of this kinase in the checkpoint response lead to the suggestion that ATR functions as a sensor of DNA lesions. After activation, ATR phosphorylates and activates the effector kinase Chk1, thereby causing an inhibition in cell cycle progression. However, this would not be possible without the existence of many other proteins operating in this pathway. Here we review current progress in our understanding of the regulatory factors involved in the ATR-mediated checkpoint response, as well as resumption of cell cycle progression upon repair of the damage, thereby focussing on the mechanisms in mammalian cells.

Disruption of Serine/Threonine Protein Phosphatase 5 (PP5:PPP5c) in Mice Reveals a Novel Role for PP5 in the Regulation of Ultraviolet Light-induced Phosphorylation of Serine/Threonine Protein Kinase Chk1 (CHEK1)

“…Therefore, we next examined events downstream of ATR activation. In response to UV light, ATR phosphorylates Chk1 (at both Ser-317 and Ser-345), which activates the kinase activity of Chk1 (5,43,44). In turn, Chk1 phosphorylates p53 (at Ser-15/ 18).…”

“…When activated, ATR phosphorylates a number of proteins that participate in the DNA damage response, and ATR-mediated phosphorylation of Chk1 at Ser-317 and Ser-345 activates Chk1-kinase activity and represents a hallmark of ATR-activation (1,5,37,38). In turn, Chk1 phosphorylates p53 (Ser-15/18 and Ser-20/23) and Cdc25A.…”

“…1 and 2). In response to genomic damage caused by reactive oxygen species, UV light, chemicals, or ionizing radiation, three PI3K-related protein kinases, ATM (ataxia-telangiectasia mutated), ATR (ataxia-telangiectasia and Rad3-related), and DNA-PKcs (DNA-dependent proteins kinase catalytic subunit) become activated (3)(4)(5)(6). Via elaborate mechanisms, these kinases phosphorylate proteins that help initiate and coordinate: 1) the recruitment of repair proteins to damaged DNA, 2) the suppression of cell cycle progression while repairs are in progress, and 3) the induction of apoptosis when damage cannot be adequately repaired.…”

Limited Repair of Critical DNA Damage in Cells Exposed to Low Dose Radiation

“…The single-strand DNA regions are loaded by molecules of the protein RPA, participating in DNA replication and these proteins provide protection of single-strand DNA from nuclease attacks. ATRkinase, in conjunction with the protein ATRIP (ATR binding protein), move to the regions with which RPA molecules are associated and covers single-strand DNA (Zou & Elledge, 2003;Smits et al, 2010). Thus, ATR, like ATM, is a transducer of the signal received from the sensors of DNA damage.…”

“…Thus, ATR, like ATM, is a transducer of the signal received from the sensors of DNA damage. ATR-kinase can be activated in cells irradiated in the S-phase (when the damage blocks DNA replication) (Cimprich and Cortez, 2008;Smits et al, 2010). Although ATM is crucial in the primary response of the cell to DNA damage and in the subsequent activation of ATR, the latter has been proved to be more important for the survival of mammals.…”