TY - JOUR
T1 - TopBP1 controls BLM protein level to maintain genome stability
AU - Wang, Jiadong
AU - Chen, Junjie
AU - Gong, Zihua
N1 - Funding Information:
We thank our colleagues in Dr. Chen’s laboratory for insightful discussions and technical assistance. We thank Dr. Lei Li at the University of Texas MD Anderson Cancer for providing WT and BLM-deficient cells. This work was supported in part by grants from the National Institutes of Health (CA089239 and CA092312 to J.C.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. J.C. is a recipient of an Era of Hope Scholar award from the United States Department of Defense (W81XWH-05-1-0470) and is a member of the MD Anderson Cancer Center, which is supported in part by the National Institutes of Health through a Cancer Center Support Grant (CA016672).
PY - 2013/12/12
Y1 - 2013/12/12
N2 - 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.
AB - 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.
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U2 - 10.1016/j.molcel.2013.10.012
DO - 10.1016/j.molcel.2013.10.012
M3 - Article
C2 - 24239288
AN - SCOPUS:84890241687
SN - 1097-2765
VL - 52
SP - 667
EP - 678
JO - Molecular cell
JF - Molecular cell
IS - 5
ER -