Stepwise activation of the ATR signaling pathway upon increasing replication stress impacts fragile site integrity.
Breaks at common fragile sites (CFS) are a recognized source of genome instability in pre-neoplastic lesions, but how such checkpoint-proficient cells escape surveillance and continue cycling is unknown. Here we show, in lymphocytes and fibroblasts, that moderate replication stresses like those indu...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC3715430?pdf=render |
| _version_ | 1819016629166538752 |
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| author | Stéphane Koundrioukoff Sandra Carignon Hervé Técher Anne Letessier Olivier Brison Michelle Debatisse |
| author_facet | Stéphane Koundrioukoff Sandra Carignon Hervé Técher Anne Letessier Olivier Brison Michelle Debatisse |
| author_sort | Stéphane Koundrioukoff |
| collection | DOAJ |
| description | Breaks at common fragile sites (CFS) are a recognized source of genome instability in pre-neoplastic lesions, but how such checkpoint-proficient cells escape surveillance and continue cycling is unknown. Here we show, in lymphocytes and fibroblasts, that moderate replication stresses like those inducing breaks at CFSs trigger chromatin loading of sensors and mediators of the ATR pathway but fail to activate Chk1 or p53. Consistently, we found that cells depleted of ATR, but not of Chk1, accumulate single-stranded DNA upon Mre11-dependent resection of collapsed forks. Partial activation of the pathway under moderate stress thus takes steps against fork disassembly but tolerates S-phase progression and mitotic onset. We show that fork protection by ATR is crucial to CFS integrity, specifically in the cell type where a given site displays paucity in backup replication origins. Tolerance to mitotic entry with under-replicated CFSs therefore results in chromosome breaks, providing a pool of cells committed to further instability. |
| first_indexed | 2024-12-21T02:50:40Z |
| format | Article |
| id | doaj.art-d484528a1312455ea70ca5c9b00c4e0a |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-21T02:50:40Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-d484528a1312455ea70ca5c9b00c4e0a2022-12-21T19:18:27ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042013-01-0197e100364310.1371/journal.pgen.1003643Stepwise activation of the ATR signaling pathway upon increasing replication stress impacts fragile site integrity.Stéphane KoundrioukoffSandra CarignonHervé TécherAnne LetessierOlivier BrisonMichelle DebatisseBreaks at common fragile sites (CFS) are a recognized source of genome instability in pre-neoplastic lesions, but how such checkpoint-proficient cells escape surveillance and continue cycling is unknown. Here we show, in lymphocytes and fibroblasts, that moderate replication stresses like those inducing breaks at CFSs trigger chromatin loading of sensors and mediators of the ATR pathway but fail to activate Chk1 or p53. Consistently, we found that cells depleted of ATR, but not of Chk1, accumulate single-stranded DNA upon Mre11-dependent resection of collapsed forks. Partial activation of the pathway under moderate stress thus takes steps against fork disassembly but tolerates S-phase progression and mitotic onset. We show that fork protection by ATR is crucial to CFS integrity, specifically in the cell type where a given site displays paucity in backup replication origins. Tolerance to mitotic entry with under-replicated CFSs therefore results in chromosome breaks, providing a pool of cells committed to further instability.http://europepmc.org/articles/PMC3715430?pdf=render |
| spellingShingle | Stéphane Koundrioukoff Sandra Carignon Hervé Técher Anne Letessier Olivier Brison Michelle Debatisse Stepwise activation of the ATR signaling pathway upon increasing replication stress impacts fragile site integrity. PLoS Genetics |
| title | Stepwise activation of the ATR signaling pathway upon increasing replication stress impacts fragile site integrity. |
| title_full | Stepwise activation of the ATR signaling pathway upon increasing replication stress impacts fragile site integrity. |
| title_fullStr | Stepwise activation of the ATR signaling pathway upon increasing replication stress impacts fragile site integrity. |
| title_full_unstemmed | Stepwise activation of the ATR signaling pathway upon increasing replication stress impacts fragile site integrity. |
| title_short | Stepwise activation of the ATR signaling pathway upon increasing replication stress impacts fragile site integrity. |
| title_sort | stepwise activation of the atr signaling pathway upon increasing replication stress impacts fragile site integrity |
| url | http://europepmc.org/articles/PMC3715430?pdf=render |
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