The DNA translocase activity of FANCM protects stalled replication forks.
FANCM is the most highly conserved protein within the Fanconi anaemia (FA) tumour suppressor pathway. However, although FANCM contains a helicase domain with translocase activity, this is not required for its role in activating the FA pathway. Instead, we show here that FANCM translocaseactivity is...
| Main Authors: | , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2012
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| _version_ | 1797052853202714624 |
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| author | Blackford, A Schwab, R Nieminuszczy, J Deans, A West, S Niedzwiedz, W |
| author_facet | Blackford, A Schwab, R Nieminuszczy, J Deans, A West, S Niedzwiedz, W |
| author_sort | Blackford, A |
| collection | OXFORD |
| description | FANCM is the most highly conserved protein within the Fanconi anaemia (FA) tumour suppressor pathway. However, although FANCM contains a helicase domain with translocase activity, this is not required for its role in activating the FA pathway. Instead, we show here that FANCM translocaseactivity is essential for promoting replication fork stability. We demonstrate that cells expressing translocase-defective FANCM show altered global replication dynamics due to increased accumulation of stalled forks that subsequently degenerate into DNA double-strand breaks, leading to ATM activation, CTBP-interacting protein (CTIP)-dependent end resection and homologous recombination repair. Accordingly, abrogation of ATM or CTIP function in FANCM-deficient cells results in decreased cell survival. We also found that FANCM translocase activity protects cells from accumulating 53BP1-OPT domains, which mark lesions resulting from problems arising during replication. Taken together, these data show that FANCM plays an essential role in maintaining chromosomal integrity by promoting the recovery of stalled replication forks and hence preventing tumourigenesis. |
| first_indexed | 2024-03-06T18:36:30Z |
| format | Journal article |
| id | oxford-uuid:0b6d6738-92bd-45fd-9ec6-2b40e4a09289 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:36:30Z |
| publishDate | 2012 |
| record_format | dspace |
| spelling | oxford-uuid:0b6d6738-92bd-45fd-9ec6-2b40e4a092892022-03-26T09:29:18ZThe DNA translocase activity of FANCM protects stalled replication forks.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:0b6d6738-92bd-45fd-9ec6-2b40e4a09289EnglishSymplectic Elements at Oxford2012Blackford, ASchwab, RNieminuszczy, JDeans, AWest, SNiedzwiedz, WFANCM is the most highly conserved protein within the Fanconi anaemia (FA) tumour suppressor pathway. However, although FANCM contains a helicase domain with translocase activity, this is not required for its role in activating the FA pathway. Instead, we show here that FANCM translocaseactivity is essential for promoting replication fork stability. We demonstrate that cells expressing translocase-defective FANCM show altered global replication dynamics due to increased accumulation of stalled forks that subsequently degenerate into DNA double-strand breaks, leading to ATM activation, CTBP-interacting protein (CTIP)-dependent end resection and homologous recombination repair. Accordingly, abrogation of ATM or CTIP function in FANCM-deficient cells results in decreased cell survival. We also found that FANCM translocase activity protects cells from accumulating 53BP1-OPT domains, which mark lesions resulting from problems arising during replication. Taken together, these data show that FANCM plays an essential role in maintaining chromosomal integrity by promoting the recovery of stalled replication forks and hence preventing tumourigenesis. |
| spellingShingle | Blackford, A Schwab, R Nieminuszczy, J Deans, A West, S Niedzwiedz, W The DNA translocase activity of FANCM protects stalled replication forks. |
| title | The DNA translocase activity of FANCM protects stalled replication forks. |
| title_full | The DNA translocase activity of FANCM protects stalled replication forks. |
| title_fullStr | The DNA translocase activity of FANCM protects stalled replication forks. |
| title_full_unstemmed | The DNA translocase activity of FANCM protects stalled replication forks. |
| title_short | The DNA translocase activity of FANCM protects stalled replication forks. |
| title_sort | dna translocase activity of fancm protects stalled replication forks |
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