DNA double strand break repair in human bladder cancer is error prone and involves microhomology-associated end-joining.
In human cells DNA double strand breaks (DSBs) can be repaired by the non-homologous end-joining (NHEJ) pathway. In a background of NHEJ deficiency, DSBs with mismatched ends can be joined by an error-prone mechanism involving joining between regions of nucleotide microhomology. The majority of join...
| Main Authors: | , , , , |
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| Format: | Journal article |
| Language: | English |
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2004
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| _version_ | 1826278284561743872 |
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| author | Bentley, J Diggle, C Harnden, P Knowles, M Kiltie, A |
| author_facet | Bentley, J Diggle, C Harnden, P Knowles, M Kiltie, A |
| author_sort | Bentley, J |
| collection | OXFORD |
| description | In human cells DNA double strand breaks (DSBs) can be repaired by the non-homologous end-joining (NHEJ) pathway. In a background of NHEJ deficiency, DSBs with mismatched ends can be joined by an error-prone mechanism involving joining between regions of nucleotide microhomology. The majority of joins formed from a DSB with partially incompatible 3' overhangs by cell-free extracts from human glioblastoma (MO59K) and urothelial (NHU) cell lines were accurate and produced by the overlap/fill-in of mismatched termini by NHEJ. However, repair of DSBs by extracts using tissue from four high-grade bladder carcinomas resulted in no accurate join formation. Junctions were formed by the non-random deletion of terminal nucleotides and showed a preference for annealing at a microhomology of 8 nt buried within the DNA substrate; this process was not dependent on functional Ku70, DNA-PK or XRCC4. Junctions were repaired in the same manner in MO59K extracts in which accurate NHEJ was inactivated by inhibition of Ku70 or DNA-PK(cs). These data indicate that bladder tumour extracts are unable to perform accurate NHEJ such that error-prone joining predominates. Therefore, in high-grade tumours mismatched DSBs are repaired by a highly mutagenic, microhomology-mediated, alternative end-joining pathway, a process that may contribute to genomic instability observed in bladder cancer. |
| first_indexed | 2024-03-06T23:41:39Z |
| format | Journal article |
| id | oxford-uuid:6f899252-9142-4190-9720-144fe258690d |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:41:39Z |
| publishDate | 2004 |
| record_format | dspace |
| spelling | oxford-uuid:6f899252-9142-4190-9720-144fe258690d2022-03-26T19:31:16ZDNA double strand break repair in human bladder cancer is error prone and involves microhomology-associated end-joining.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:6f899252-9142-4190-9720-144fe258690dEnglishSymplectic Elements at Oxford2004Bentley, JDiggle, CHarnden, PKnowles, MKiltie, AIn human cells DNA double strand breaks (DSBs) can be repaired by the non-homologous end-joining (NHEJ) pathway. In a background of NHEJ deficiency, DSBs with mismatched ends can be joined by an error-prone mechanism involving joining between regions of nucleotide microhomology. The majority of joins formed from a DSB with partially incompatible 3' overhangs by cell-free extracts from human glioblastoma (MO59K) and urothelial (NHU) cell lines were accurate and produced by the overlap/fill-in of mismatched termini by NHEJ. However, repair of DSBs by extracts using tissue from four high-grade bladder carcinomas resulted in no accurate join formation. Junctions were formed by the non-random deletion of terminal nucleotides and showed a preference for annealing at a microhomology of 8 nt buried within the DNA substrate; this process was not dependent on functional Ku70, DNA-PK or XRCC4. Junctions were repaired in the same manner in MO59K extracts in which accurate NHEJ was inactivated by inhibition of Ku70 or DNA-PK(cs). These data indicate that bladder tumour extracts are unable to perform accurate NHEJ such that error-prone joining predominates. Therefore, in high-grade tumours mismatched DSBs are repaired by a highly mutagenic, microhomology-mediated, alternative end-joining pathway, a process that may contribute to genomic instability observed in bladder cancer. |
| spellingShingle | Bentley, J Diggle, C Harnden, P Knowles, M Kiltie, A DNA double strand break repair in human bladder cancer is error prone and involves microhomology-associated end-joining. |
| title | DNA double strand break repair in human bladder cancer is error prone and involves microhomology-associated end-joining. |
| title_full | DNA double strand break repair in human bladder cancer is error prone and involves microhomology-associated end-joining. |
| title_fullStr | DNA double strand break repair in human bladder cancer is error prone and involves microhomology-associated end-joining. |
| title_full_unstemmed | DNA double strand break repair in human bladder cancer is error prone and involves microhomology-associated end-joining. |
| title_short | DNA double strand break repair in human bladder cancer is error prone and involves microhomology-associated end-joining. |
| title_sort | dna double strand break repair in human bladder cancer is error prone and involves microhomology associated end joining |
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