Multiple ATR-Chk1 pathway proteins preferentially associate with checkpoint-inducing DNA substrates.
The ATR-Chk1 DNA damage checkpoint pathway is a critical regulator of the cellular response to DNA damage and replication stress in human cells. The variety of environmental, chemotherapeutic, and carcinogenic agents that activate this signal transduction pathway do so primarily through the formatio...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2011-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3146532?pdf=render |
| _version_ | 1818016005960499200 |
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| author | Seçil Yilmaz Aziz Sancar Michael G Kemp |
| author_facet | Seçil Yilmaz Aziz Sancar Michael G Kemp |
| author_sort | Seçil Yilmaz |
| collection | DOAJ |
| description | The ATR-Chk1 DNA damage checkpoint pathway is a critical regulator of the cellular response to DNA damage and replication stress in human cells. The variety of environmental, chemotherapeutic, and carcinogenic agents that activate this signal transduction pathway do so primarily through the formation of bulky adducts in DNA and subsequent effects on DNA replication fork progression. Because there are many protein-protein and protein-DNA interactions proposed to be involved in activation and/or maintenance of ATR-Chk1 signaling in vivo, we systematically analyzed the association of a number of ATR-Chk1 pathway proteins with relevant checkpoint-inducing DNA structures in vitro. These DNA substrates included single-stranded DNA, branched DNA, and bulky adduct-containing DNA. We found that many checkpoint proteins show a preference for single-stranded, branched, and bulky adduct-containing DNA in comparison to undamaged, double-stranded DNA. We additionally found that the association of checkpoint proteins with bulky DNA damage relative to undamaged DNA was strongly influenced by the ionic strength of the binding reaction. Interestingly, among the checkpoint proteins analyzed the checkpoint mediator proteins Tipin and Claspin showed the greatest differential affinity for checkpoint-inducing DNA structures. We conclude that the association and accumulation of multiple checkpoint proteins with DNA structures indicative of DNA damage and replication stress likely contribute to optimal ATR-Chk1 DNA damage checkpoint responses. |
| first_indexed | 2024-04-14T07:05:52Z |
| format | Article |
| id | doaj.art-83aaec6ddeb14068a3c9959b24eb77e9 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-14T07:05:52Z |
| publishDate | 2011-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-83aaec6ddeb14068a3c9959b24eb77e92022-12-22T02:06:34ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-01-0167e2298610.1371/journal.pone.0022986Multiple ATR-Chk1 pathway proteins preferentially associate with checkpoint-inducing DNA substrates.Seçil YilmazAziz SancarMichael G KempThe ATR-Chk1 DNA damage checkpoint pathway is a critical regulator of the cellular response to DNA damage and replication stress in human cells. The variety of environmental, chemotherapeutic, and carcinogenic agents that activate this signal transduction pathway do so primarily through the formation of bulky adducts in DNA and subsequent effects on DNA replication fork progression. Because there are many protein-protein and protein-DNA interactions proposed to be involved in activation and/or maintenance of ATR-Chk1 signaling in vivo, we systematically analyzed the association of a number of ATR-Chk1 pathway proteins with relevant checkpoint-inducing DNA structures in vitro. These DNA substrates included single-stranded DNA, branched DNA, and bulky adduct-containing DNA. We found that many checkpoint proteins show a preference for single-stranded, branched, and bulky adduct-containing DNA in comparison to undamaged, double-stranded DNA. We additionally found that the association of checkpoint proteins with bulky DNA damage relative to undamaged DNA was strongly influenced by the ionic strength of the binding reaction. Interestingly, among the checkpoint proteins analyzed the checkpoint mediator proteins Tipin and Claspin showed the greatest differential affinity for checkpoint-inducing DNA structures. We conclude that the association and accumulation of multiple checkpoint proteins with DNA structures indicative of DNA damage and replication stress likely contribute to optimal ATR-Chk1 DNA damage checkpoint responses.http://europepmc.org/articles/PMC3146532?pdf=render |
| spellingShingle | Seçil Yilmaz Aziz Sancar Michael G Kemp Multiple ATR-Chk1 pathway proteins preferentially associate with checkpoint-inducing DNA substrates. PLoS ONE |
| title | Multiple ATR-Chk1 pathway proteins preferentially associate with checkpoint-inducing DNA substrates. |
| title_full | Multiple ATR-Chk1 pathway proteins preferentially associate with checkpoint-inducing DNA substrates. |
| title_fullStr | Multiple ATR-Chk1 pathway proteins preferentially associate with checkpoint-inducing DNA substrates. |
| title_full_unstemmed | Multiple ATR-Chk1 pathway proteins preferentially associate with checkpoint-inducing DNA substrates. |
| title_short | Multiple ATR-Chk1 pathway proteins preferentially associate with checkpoint-inducing DNA substrates. |
| title_sort | multiple atr chk1 pathway proteins preferentially associate with checkpoint inducing dna substrates |
| url | http://europepmc.org/articles/PMC3146532?pdf=render |
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