scholarly journals The Tumor Suppressor MIG6 Controls Mitotic Progression and the G2/M DNA Damage Checkpoint by Stabilizing the WEE1 Kinase

Cell Reports ◽  
2018 ◽  
Vol 24 (5) ◽  
pp. 1278-1289 ◽  
Author(s):  
Mari Sasaki ◽  
Takeshi Terabayashi ◽  
Stefanie M. Weiss ◽  
Ingvar Ferby
Keyword(s):  
Dna Damage ◽  
Tumor Suppressor ◽  
Dna Damage Checkpoint ◽  
Mitotic Progression ◽  
Wee1 Kinase

scholarly journals LATS1/WARTS phosphorylates MYPT1 to counteract PLK1 and regulate mammalian mitotic progression

2012 ◽  
Vol 197 (5) ◽  
pp. 625-641 ◽  
Author(s):  
Tatsuyuki Chiyoda ◽  
Naoyuki Sugiyama ◽  
Takatsune Shimizu ◽  
Hideaki Naoe ◽  
Yusuke Kobayashi ◽  
...  
Keyword(s):  
Dna Damage ◽  
Deoxyribonucleic Acid ◽  
Mitotic Exit ◽  
Dna Damage Checkpoint ◽  
Mitotic Progression ◽  
Myosin Phosphatase ◽  
G2 Checkpoint ◽  
Mitotic Exit Network ◽  
Kinase Screening

In the mitotic exit network of budding yeast, Dbf2 kinase phosphorylates and regulates Cdc14 phosphatase. In contrast, no phosphatase substrates of LATS1/WARTS kinase, the mammalian equivalent of Dbf2, has been reported. To address this discrepancy, we performed phosphoproteomic screening using LATS1 kinase. Screening identified MYPT1 (myosin phosphatase–targeting subunit 1) as a new substrate for LATS1. LATS1 directly and preferentially phosphorylated serine 445 (S445) of MYPT1. An MYPT1 mutant (S445A) failed to dephosphorylate Thr 210 of PLK1 (pololike kinase 1), thereby activating PLK1. This suggests that LATS1 promotes MYPT1 to antagonize PLK1 activity. Consistent with this, LATS1-depleted HeLa cells or fibroblasts from LATS1 knockout mice showed increased PLK1 activity. We also found deoxyribonucleic acid (DNA) damage–induced LATS1 activation caused PLK1 suppression via the phosphorylation of MYPT1 S445. Furthermore, LATS1 knockdown cells showed reduced G2 checkpoint arrest after DNA damage. These results indicate that LATS1 phosphorylates a phosphatase as does the yeast Dbf2 and demonstrate a novel role of LATS1 in controlling PLK1 at the G2 DNA damage checkpoint.

scholarly journals Proteins in the Nutrient-Sensing and DNA Damage Checkpoint Pathways Cooperate to Restrain Mitotic Progression following DNA Damage

PLoS Genetics ◽  
2011 ◽  
Vol 7 (7) ◽  
pp. e1002176 ◽  
Author(s):  
Jennifer S. Searle ◽  
Matthew D. Wood ◽  
Mandeep Kaur ◽  
David V. Tobin ◽  
Yolanda Sanchez
Keyword(s):  
Dna Damage ◽  
Nutrient Sensing ◽  
Dna Damage Checkpoint ◽  
Mitotic Progression

The DNA damage checkpoint and PKA pathways converge on APC substrates and Cdc20 to regulate mitotic progression

2004 ◽  
Vol 6 (2) ◽  
pp. 138-145 ◽  
Author(s):  
Jennifer S. Searle ◽  
Kaila L. Schollaert ◽  
Benjamin J. Wilkins ◽  
Yolanda Sanchez
Keyword(s):  
Dna Damage ◽  
Dna Damage Checkpoint ◽  
Mitotic Progression

scholarly journals Mediator of DNA damage checkpoint 1 (MDC1) is a novel estrogen receptor co-regulator in invasive lobular carcinoma of the breast

2020 ◽  
Author(s):  
Evelyn K. Bordeaux ◽  
Joseph L. Sottnik ◽  
Sanjana Mehrotra ◽  
Sarah E. Ferrara ◽  
Andrew E. Goodspeed ◽  
...  
Keyword(s):  
Dna Damage ◽  
Estrogen Receptor ◽  
Tumor Suppressor ◽  
Cell Lines ◽  
Invasive Lobular Carcinoma ◽  
Ductal Carcinoma ◽  
Lobular Carcinoma ◽  
Laboratory Data ◽  
Published Data ◽  
Dna Damage Checkpoint

ABSTRACTInvasive lobular carcinoma (ILC) is the most common histological subtype of breast cancer, and nearly all ILC tumors express estrogen receptor alpha (ER). However, clinical and laboratory data suggest ILC are strongly estrogen-driven but not equally sensitive to anti-estrogen therapies. We hypothesized that ILC-specific ER transcriptional co-regulators mediate ER functions in ILC and anti-estrogen resistance, and profiled ER-associated proteins by mass spectrometry. Three ER+ ILC cell lines, MDA MB 134VI, SUM44PE, and BCK4, were compared to published data from ER+ invasive ductal carcinoma (IDC) cell lines, and we examined whether siRNA knockdown of identified proteins suppressed ER-driven proliferation in ILC cells. This approach found mediator of DNA damage checkpoint 1 (MDC1), a key tumor suppressor in DNA damage response (DDR), as a putative novel ER co-regulator in ILC. We confirmed ER:MDC1 interaction was specific to ILC cell lines versus IDC cells, and found MDC1 knockdown suppressed ILC cell proliferation and suppressed tamoxifen resistance in MDA MB 134VI. Using RNA-sequencing, we found that in ILC cells, MDC1 knockdown broadly dysregulates the estrogen-driven ER transcriptome, with ER:MDC1 target genes enriched for hormone-response-elements in their promoter regions. Importantly, our data are inconsistent with MDC1 regulating ER via MDC1 DDR and tumor suppressor functions, but instead suggest a novel oncogenic role for MDC1 in mediating ER transcriptional activity as a co-regulator. Supporting this, in breast tumor tissue microarrays MDC1 protein was frequently low or absent in IDC or ER-ILC, but MDC1 loss is rare in ER+ ILC. ER:MDC1 interaction and MDC1 co-regulator functions may underlie cell type-specific ER functions in ILC, and serve as important biomarkers and therapeutic targets to overcome anti-estrogen resistance in ILC.

scholarly journals Aberrant monomethylation of histone H4 lysine 20 activates the DNA damage checkpoint in Drosophila melanogaster

2007 ◽  
Vol 176 (2) ◽  
pp. 155-162 ◽  
Author(s):  
Ayako Sakaguchi ◽  
Ruth Steward
Keyword(s):  
Dna Damage ◽  
Double Mutant ◽  
Chromosome Condensation ◽  
Cyclin B ◽  
Order Structure ◽  
Dna Damage Checkpoint ◽  
Histone H4 ◽  
Mitotic Progression ◽  
Strong Reduction ◽  
Early Mitosis

PR-Set7 is a histone methyltransferase that specifically monomethylates histone H4 lysine 20 (K20) and is essential for cell proliferation. Our results show that in PR-Set7 mutants, the DNA damage checkpoint is activated. This phenotype is manifested by reduction in both the mitotic and the S phase indexes, a delay in the progression through early mitosis, and strong reduction of cyclin B. Furthermore, in a double mutant of PR-Set7 and mei-41 (the fly ATR orthologue), the abnormalities of mitotic progression and the cyclin B protein level were rescued. PR-Set7 also showed a defect in chromosome condensation that was enhanced in the double mutant. We therefore propose that monomethylated H4K20 is involved in the maintenance of proper higher order structure of DNA and is consequently essential for chromosome condensation.

scholarly journals Mediator of DNA Damage Checkpoint 1 (MDC1) Regulates Mitotic Progression

2009 ◽  
Vol 284 (49) ◽  
pp. 33939-33948 ◽  
Author(s):  
Kelly Townsend ◽  
Helen Mason ◽  
Andrew N. Blackford ◽  
Edward S. Miller ◽  
J. Ross Chapman ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Checkpoint ◽  
Mitotic Progression

scholarly journals Mutation of DNA primase causes extensive apoptosis of retinal neurons through the activation of DNA damage checkpoint and tumor suppressor p53

Development ◽  
2008 ◽  
Vol 135 (7) ◽  
pp. 1247-1257 ◽  
Author(s):  
M. Yamaguchi ◽  
N. Fujimori-Tonou ◽  
Y. Yoshimura ◽  
T. Kishi ◽  
H. Okamoto ◽  
...  
Keyword(s):  
Dna Damage ◽  
Tumor Suppressor ◽  
Dna Damage Checkpoint ◽  
Retinal Neurons ◽  
Tumor Suppressor P53 ◽  
Dna Primase
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