title: UV-induced G2 checkpoint depends on p38 MAPK and minimal activation of ATR-Chk1 pathway.
abstract: In response to UV light, single-stranded DNA intermediates coated with replication protein A (RPA) are generated, which trigger the ATR-Chk1 checkpoint pathway. Recruitment and/or activation of several checkpoint proteins at the damaged sites is important for the subsequent cell cycle arrest. Surprisingly, upon UV irradiation, Rad9 and RPA only minimally accumulate at DNA lesions in G2 phase, suggesting that only a few single-stranded DNA intermediates are generated. Also, little phosphorylated Chk1 is observed in G2 phase after UV-irradiation, and UV light fails to elicit efficient accumulation of typical DNA damage response proteins at sites of damage in this phase. By contrast, p38 MAPK is phosphorylated in G2 phase cells after UV damage. Interestingly, despite the lack of an obvious activation of the ATR-Chk1 pathway, only the combined inhibition of the ATR- and p38-dependent pathways results in a complete abrogation of the UV-induced G2/M arrest. This suggests that UV light induces less hazardous lesions in G2 phase or that lesions created in this phase are less efficiently processed, resulting in a low activation of the ATR-Chk1 pathway. UV-induced G2 checkpoint activation in this situation therefore relies on signalling via the p38 MAPK and ATR-Chk1 signalling cascades.
authors: Department of Cell Biology and Genetics, Cancer Genomics Center, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands. d.warmerdam@nki.nl; vsmits@ull.es
authors: Daniël O
authors: DO
authors: Warmerdam
authors: Eva K
authors: EK
authors: Brinkman
authors: Jurgen A
authors: JA
authors: Marteijn
authors: René H
authors: RH
authors: Medema
authors: Roland
authors: R
authors: Kanaar
authors: Veronique A J
authors: VA
authors: Smits
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D000071877:Checkpoint Kinase 1; D053904:DNA Breaks, Single-Stranded / Q000528:radiation effects; D059565:G2 Phase Cell Cycle Checkpoints / Q000235:genetics / Q000528:radiation effects*; D006367:HeLa Cells; D006801:Humans; D010766:Phosphorylation / Q000235:genetics / Q000528:radiation effects; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051716:Replication Protein A / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000528:radiation effects*; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D051716:Replication Protein A; C069930:rad9 protein; D011494:Protein Kinases; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: ATR; Chk1; G2 phase; UV; p38