c-Myc accelerates S-phase and requires WRN to avoid replication stress.
c-Myc interacts with components of the pre-replication complex and directly regulates DNA replication [1]. However the consequences of this novel c-Myc function on cell cycle dynamics and replication-associated damage are unknown. Here, we show that c-Myc overexpression in primary human fibroblasts...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2009-06-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC2694031?pdf=render |
| _version_ | 1818136643566043136 |
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| author | Kristin Robinson Nichaya Asawachaicharn Denise A Galloway Carla Grandori |
| author_facet | Kristin Robinson Nichaya Asawachaicharn Denise A Galloway Carla Grandori |
| author_sort | Kristin Robinson |
| collection | DOAJ |
| description | c-Myc interacts with components of the pre-replication complex and directly regulates DNA replication [1]. However the consequences of this novel c-Myc function on cell cycle dynamics and replication-associated damage are unknown. Here, we show that c-Myc overexpression in primary human fibroblasts markedly accelerates S-phase while c-Myc deficient fibroblasts exhibit a prolonged S-phase. We also show that the Werner DNA helicase protein (WRN) plays a critical role in supporting c-Myc-driven S-phase, as depletion of WRN in c-Myc overexpressing cells increases DNA damage specifically at sites of DNA synthesis. This excess DNA damage activates a "replication stress" pathway involving ATR, CHK1, CHK2, and p53, leading to rapid senescence of WRN deficient c-Myc overexpressing cells. Indeed, depletion of p53 rescues this senescence response. We propose that WRN functions to repair abnormal replication structures caused by the acceleration of DNA replication by c-Myc. This work provides an additional mechanistic explanation for c-Myc-induced DNA damage and senescence, and reveals a vulnerability of c-Myc overexpressing cells that could potentially be exploited in cancer therapy. |
| first_indexed | 2024-12-11T09:43:40Z |
| format | Article |
| id | doaj.art-c19ed742e9c34a96a5add399c0e9ca5b |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-11T09:43:40Z |
| publishDate | 2009-06-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-c19ed742e9c34a96a5add399c0e9ca5b2022-12-22T01:12:37ZengPublic Library of Science (PLoS)PLoS ONE1932-62032009-06-0146e595110.1371/journal.pone.0005951c-Myc accelerates S-phase and requires WRN to avoid replication stress.Kristin RobinsonNichaya AsawachaicharnDenise A GallowayCarla Grandoric-Myc interacts with components of the pre-replication complex and directly regulates DNA replication [1]. However the consequences of this novel c-Myc function on cell cycle dynamics and replication-associated damage are unknown. Here, we show that c-Myc overexpression in primary human fibroblasts markedly accelerates S-phase while c-Myc deficient fibroblasts exhibit a prolonged S-phase. We also show that the Werner DNA helicase protein (WRN) plays a critical role in supporting c-Myc-driven S-phase, as depletion of WRN in c-Myc overexpressing cells increases DNA damage specifically at sites of DNA synthesis. This excess DNA damage activates a "replication stress" pathway involving ATR, CHK1, CHK2, and p53, leading to rapid senescence of WRN deficient c-Myc overexpressing cells. Indeed, depletion of p53 rescues this senescence response. We propose that WRN functions to repair abnormal replication structures caused by the acceleration of DNA replication by c-Myc. This work provides an additional mechanistic explanation for c-Myc-induced DNA damage and senescence, and reveals a vulnerability of c-Myc overexpressing cells that could potentially be exploited in cancer therapy.http://europepmc.org/articles/PMC2694031?pdf=render |
| spellingShingle | Kristin Robinson Nichaya Asawachaicharn Denise A Galloway Carla Grandori c-Myc accelerates S-phase and requires WRN to avoid replication stress. PLoS ONE |
| title | c-Myc accelerates S-phase and requires WRN to avoid replication stress. |
| title_full | c-Myc accelerates S-phase and requires WRN to avoid replication stress. |
| title_fullStr | c-Myc accelerates S-phase and requires WRN to avoid replication stress. |
| title_full_unstemmed | c-Myc accelerates S-phase and requires WRN to avoid replication stress. |
| title_short | c-Myc accelerates S-phase and requires WRN to avoid replication stress. |
| title_sort | c myc accelerates s phase and requires wrn to avoid replication stress |
| url | http://europepmc.org/articles/PMC2694031?pdf=render |
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