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Opposing effects of the UV lesion repair protein XPA and UV bypass polymerase eta on ATR checkpoint signaling.


ABSTRACT: An essential component of the ATR (ataxia telangiectasia-mutated and Rad3-related)-activating structure is single-stranded DNA. It has been suggested that nucleotide excision repair (NER) can lead to activation of ATR by generating such a signal, and in yeast, DNA damage processing through the NER pathway is necessary for checkpoint activation during G1. We show here that ultraviolet (UV) radiation-induced ATR signaling is compromised in XPA-deficient human cells during S phase, as shown by defects in ATRIP (ATR-interacting protein) translocation to sites of UV damage, UV-induced phosphorylation of Chk1 and UV-induced replication protein A phosphorylation and chromatin binding. However, ATR signaling was not compromised in XPC-, CSB-, XPF- and XPG-deficient cells. These results indicate that damage processing is not necessary for ATR-mediated S-phase checkpoint activation and that the lesion recognition function of XPA may be sufficient. In contrast, XP-V cells deficient in the UV bypass polymerase eta exhibited enhanced ATR signaling. Taken together, these results suggest that lesion bypass and not lesion repair may raise the level of UV damage that can be tolerated before checkpoint activation, and that XPA plays a critical role in this activation.

SUBMITTER: Bomgarden RD 

PROVIDER: S-EPMC1478198 | biostudies-literature | 2006 Jun

REPOSITORIES: biostudies-literature

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Opposing effects of the UV lesion repair protein XPA and UV bypass polymerase eta on ATR checkpoint signaling.

Bomgarden Ryan D RD   Lupardus Patrick J PJ   Soni Deena V DV   Yee Muh-Ching MC   Ford James M JM   Cimprich Karlene A KA  

The EMBO journal 20060504 11


An essential component of the ATR (ataxia telangiectasia-mutated and Rad3-related)-activating structure is single-stranded DNA. It has been suggested that nucleotide excision repair (NER) can lead to activation of ATR by generating such a signal, and in yeast, DNA damage processing through the NER pathway is necessary for checkpoint activation during G1. We show here that ultraviolet (UV) radiation-induced ATR signaling is compromised in XPA-deficient human cells during S phase, as shown by defe  ...[more]

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