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Break-induced replication promotes fragile telomere formation
- Source :
- Genes Dev
- Publication Year :
- 2020
- Publisher :
- Cold Spring Harbor Laboratory, 2020.
-
Abstract
- TRF1 facilitates the replication of telomeric DNA in part by recruiting the BLM helicase, which can resolve G-quadruplexes on the lagging-strand template. Lagging-strand telomeres lacking TRF1 or BLM form fragile telomeres—structures that resemble common fragile sites (CFSs)—but how they are formed is not known. We report that analogous to CFSs, fragile telomeres in BLM-deficient cells involved double-strand break (DSB) formation, in this case by the SLX4/SLX1 nuclease. The DSBs were repaired by POLD3/POLD4-dependent break-induced replication (BIR), resulting in fragile telomeres containing conservatively replicated DNA. BIR also promoted fragile telomere formation in cells with FokI-induced telomeric DSBs and in alternative lengthening of telomeres (ALT) cells, which have spontaneous telomeric damage. BIR of telomeric DSBs competed with PARP1-, LIG3-, and XPF-dependent alternative nonhomologous end joining (alt-NHEJ), which did not generate fragile telomeres. Collectively, these findings indicate that fragile telomeres can arise from BIR-mediated repair of telomeric DSBs.
- Subjects :
- DNA Replication
DNA Repair
LIG3
Cell Line
Recombinases
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
PARP1
Genetics
Animals
Humans
DNA Breaks, Double-Stranded
Cells, Cultured
030304 developmental biology
0303 health sciences
Nuclease
Endodeoxyribonucleases
RecQ Helicases
biology
Chromosome Fragile Sites
Chromosomal fragile site
fungi
Helicase
Fibroblasts
Telomere
Cell biology
Non-homologous end joining
chemistry
030220 oncology & carcinogenesis
biology.protein
DNA
Research Paper
Developmental Biology
Subjects
Details
- ISSN :
- 15495477 and 08909369
- Volume :
- 34
- Database :
- OpenAIRE
- Journal :
- Genes & Development
- Accession number :
- edsair.doi.dedup.....463296cfcc9b790548e61a9a09010dd9