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TopBP1 controls BLM protein level to maintain genome stability.
- Source :
-
Molecular cell [Mol Cell] 2013 Dec 12; Vol. 52 (5), pp. 667-78. Date of Electronic Publication: 2013 Nov 14. - Publication Year :
- 2013
-
Abstract
- Human TopBP1 is a key mediator protein involved in DNA replication checkpoint control. In this study, we report a specific interaction between TopBP1 and Bloom syndrome helicase (BLM) that is phosphorylation and cell-cycle dependent. Interestingly, TopBP1 depletion led to decreased BLM protein level and increased sister chromatid exchange (SCE). Moreover, our data indicated that BLM was ubiquitinated by E3 ligase MIB1 and degraded in G1 cells but was stabilized by TopBP1 in S phase cells. Depletion of MIB1 restored BLM protein level and rescued the elevated SCE phenotype in TopBP1-depleted cells. In addition, cells expressing an undegradable BLM mutant showed radiation sensitivity, probably by triggering end resection and inhibiting the nonhomologous end-joining (NHEJ) pathway in G1 phase. Altogether, these data suggest that, although BLM is downregulated in G1 phase in order to promote NHEJ-mediated DNA repair, it is stabilized by TopBP1 in S phase cells in order to suppress SCE and thereby prevent genomic instability.<br /> (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Subjects :
- Cell Line
Cell Line, Tumor
DNA End-Joining Repair
Down-Regulation
G1 Phase genetics
HEK293 Cells
HeLa Cells
Humans
Phosphorylation
S Phase genetics
Sister Chromatid Exchange
Ubiquitin-Protein Ligases genetics
Ubiquitin-Protein Ligases metabolism
Carrier Proteins genetics
Carrier Proteins metabolism
DNA-Binding Proteins genetics
DNA-Binding Proteins metabolism
Genomic Instability
Nuclear Proteins genetics
Nuclear Proteins metabolism
RecQ Helicases genetics
RecQ Helicases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4164
- Volume :
- 52
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Molecular cell
- Publication Type :
- Academic Journal
- Accession number :
- 24239288
- Full Text :
- https://doi.org/10.1016/j.molcel.2013.10.012