|
| Status |
Public on Nov 23, 2017 |
| Title |
BRCA1 suppresses microhomology-mediated tandem duplications at Tus/Ter-stalled replication forks |
| Organism |
Mus musculus |
| Experiment type |
Other
|
| Summary |
Small ~10 kb microhomology-mediated tandem duplications (“Group 1 TDs”) are abundant in BRCA1-linked but not BRCA2-linked breast cancer genomes. Here, we define the mechanism underlying this rearrangement signature. We show that BRCA1, but not BRCA2, suppresses TDs at a Tus/Ter site-specific chromosomal replication fork barrier in primary mammalian cells. BRCA1 has no equivalent role at chromosomal double strand breaks, indicating specificity for the stalled fork response. Two motor proteins—FANCM and the Bloom’s syndrome helicase—suppress Tus/Ter-induced TDs in BRCA1 mutants, revealing the existence of a multi-gene TD suppressor network. TDs arise by a “replication restart-bypass” mechanism terminated by end joining or microhomology-mediated template switching, the latter forming complex TD breakpoints. We show that solitary DNA ends form directly at Tus/Ter, implicating misrepair of these lesions in TD formation. We find that BRCA1 inactivation is strongly associated with Group 1 TDs in ovarian cancer. The Group 1 TD phenotype may be a general signature of BRCA1-deficient cancer
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| |
|
| Overall design |
LAM-HTGTS from a Cas9/gRNA bait DSB 30kb away from the 1xGFP Ter array cassette inserted in the ROSA26 locus
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| |
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| Contributor(s) |
Willis NA, Frock RL, Alt FW, Scully R |
| Citation(s) |
29168504 |
| Submission date |
Sep 08, 2017 |
| Last update date |
May 15, 2019 |
| Contact name |
Richard L Frock |
| E-mail(s) |
frock@stanford.edu
|
| Organization name |
Stanford University
|
| Department |
Radiation Oncology
|
| Lab |
Frock Lab
|
| Street address |
269 Campus Drive
|
| City |
Stanford |
| State/province |
California |
| ZIP/Postal code |
94305 |
| Country |
USA |
| |
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| Platforms (1) |
|
| Samples (25)
|
|
| Relations |
| BioProject |
PRJNA403795 |
| SRA |
SRP117142 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE103624_EV_BRCA1del_siFANCM_s2.txt.gz |
12.5 Kb |
(ftp)(http) |
TXT |
| GSE103624_ISceI_BRCA1del_siFANCM_s2.txt.gz |
49.4 Kb |
(ftp)(http) |
TXT |
| GSE103624_Tus_BRCA1del_siBLM_s3.txt.gz |
42.5 Kb |
(ftp)(http) |
TXT |
| GSE103624_Tus_BRCA1del_siBRCA1_s3.txt.gz |
41.0 Kb |
(ftp)(http) |
TXT |
| GSE103624_Tus_BRCA1del_siFANCM_s3.txt.gz |
42.9 Kb |
(ftp)(http) |
TXT |
| GSE103624_Tus_BRCA1del_siLuciferase_s3.txt.gz |
43.7 Kb |
(ftp)(http) |
TXT |
| GSE103624_Tus_BRCA1flox_siBLM_s2.txt.gz |
29.6 Kb |
(ftp)(http) |
TXT |
| GSE103624_Tus_BRCA1flox_siBRCA1_s2.txt.gz |
28.2 Kb |
(ftp)(http) |
TXT |
| GSE103624_Tus_BRCA1flox_siFANCM_s3.txt.gz |
43.9 Kb |
(ftp)(http) |
TXT |
| GSE103624_Tus_BRCA1flox_siLuciferase_s2.txt.gz |
38.7 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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