Supreme EnLIGHTenment: damage recognition and signaling in the mammalian UV response

Abstract

Like their prokaryotic counterparts, mammalian cells can sense light, especially in the ultraviolet (UV) range of the spectrum. After UV exposure, cells mount an elaborate response--called the UV response--that mimics physiological signaling responses except that it targets multiple pathways, thereby lacking the defined specificity of receptor-triggered signal transduction. Despite many years of research, it is still not fully clear how UV radiation is sensed and converted into the "language of cells"--signal reception and transduction. This review focuses on how photonic energy and its primary cellular products are sensed to elicit the UV response.

Fig 1. DNA damage induced signaling by UVR

UVR induces DNA damage, which is detected by sensor proteins such as the MRN (Mre11, Rad50 and Nbs1) complex, ATRIP (ATR interacting protein), presumably in conjunction with additional factors. A common intermediate in damage recognition seems to be single stranded DNA (ssDNA). Subsequent activation of the apical kinases ATM and ATR transduce the signal to the effector and checkpoint kinases Chk1and Chk2. For more details see text.

Fig 2. Signal tranduction in response to ultraviolet irradiation (UVR)

UVR acts on primary targets, namely protein tyrosine phosphatases, ribosomes and DNA, which via intermediate and mostly poorly defined signaling cascades, increase protein kinase activities. The type and activation level of target effector molecules, which determine cellular fate, might depend on UVR dose and type of UV-induced damage. RTK: receptor tyrosine kinase; PTP: protein tyrosine phosphatase.

Fig 3. Protein kinase and effector pathways in the mammalian UV response. (A) Mitogen activated protein kinase cascade (MAPK)

Extra-cellular signals, e.g. growth factors, and stress, e.g. UVR, respectively, stimulate a protein kinase cascade ultimately activating MAPKs and directing their nuclear translocation. The MAPK family comprises extra-cellular signal activated protein kinase (ERK) and stress activated protein kinases (SAPKs) which are preferentially activated by physiological or stress stimuli, respectively. Nuclear MAPKs phosphorylate and increase the action of transription factors, e.g. c-Jun, resulting in gene expression changes. (B) The NF-κB pathway: The trancription factor NF-κB is sequestered and inactivated by association with the inhibitor of κB (I-κB) in the cytosol. In response to, e.g. cytokines or UVR, the I–κB kinase (IKK) and, in conjunction with p38, casein kinase 2 (CK2), respectively, phosphorylate I–κB at different serine/threonine residues targeting it for degradation. This releases NF–κB to enter the nucleus and to regulate gene expression. MAPKKK: MAPK kinase kinase; MAPKK: MAPK kinase; MAPK: MAP kinase.