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 ◽  
...  

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.

2009 ◽  
Vol 37 (4) ◽  
pp. 897-904 ◽  
Author(s):  
Jennifer E. FitzGerald ◽  
Muriel Grenon ◽  
Noel F. Lowndes

53BP1 (p53-binding protein 1) is classified as a mediator/adaptor of the DNA-damage response, and is recruited to nuclear structures termed foci following genotoxic insult. In the present paper, we review the functions of 53BP1 in DNA-damage checkpoint activation and DNA repair, and the mechanisms of its recruitment and activation following DNA damage. We focus in particular on the role of covalent histone modifications in this process.


2004 ◽  
Vol 15 (4) ◽  
pp. 1568-1579 ◽  
Author(s):  
David Perera ◽  
Livia Perez-Hidalgo ◽  
Peter B. Moens ◽  
Kaarina Reini ◽  
Nicholas Lakin ◽  
...  

Mammalian TopBP1 is a BRCT domain–containing protein whose function in mitotic cells is linked to replication and DNA damage checkpoint. Here, we study its possible role during meiosis in mice. TopBP1 foci are abundant during early prophase I and localize mainly to histone γ-H2AX–positive domains, where DNA double–strand breaks (required to initiate recombination) occur. Strikingly, TopBP1 showed a pattern almost identical to that of ATR, a PI3K-like kinase involved in mitotic DNA damage checkpoint. In the synapsis-defective Fkbp6-/- mouse, TopBP1 heavily stains unsynapsed regions of chromosomes. We also tested whether Schizosaccharomyces pombe Cut5 (the TopBP1 homologue) plays a role in the meiotic recombination checkpoint, like spRad3, the ATR homologue. Indeed, we found that a cut5 mutation suppresses the checkpoint-dependent meiotic delay of a meiotic recombination defective mutant, indicating a direct role of the Cut5 protein in the meiotic checkpoint. Our findings suggest that ATR and TopBP1 monitor meiotic recombination and are required for activation of the meiotic recombination checkpoint.


2014 ◽  
Vol 56 (5) ◽  
pp. 681-695 ◽  
Author(s):  
Tongzheng Liu ◽  
Yi-Hui Lin ◽  
Wenchuan Leng ◽  
Sung Yun Jung ◽  
Haoxing Zhang ◽  
...  

PLoS Genetics ◽  
2011 ◽  
Vol 7 (7) ◽  
pp. e1002176 ◽  
Author(s):  
Jennifer S. Searle ◽  
Matthew D. Wood ◽  
Mandeep Kaur ◽  
David V. Tobin ◽  
Yolanda Sanchez

2003 ◽  
Vol 23 (14) ◽  
pp. 5018-5030 ◽  
Author(s):  
Allison J. Bardin ◽  
Monica G. Boselli ◽  
Angelika Amon

ABSTRACT The mitotic exit network (MEN), a Ras-like signaling cascade, promotes the release of the protein phosphatase Cdc14 from the nucleolus and is essential for cells to exit from mitosis in Saccharomyces cerevisiae. We have characterized the functional domains of one of the MEN components, the protein kinase Cdc15, and investigated the role of these domains in mitotic exit. We show that a region adjacent to Cdc15's kinase domain is required for self-association and for binding to spindle pole bodies and that this domain is essential for CDC15 function. Furthermore, we find that overexpression of CDC15 lacking the C-terminal 224 amino acids results in hyperactivation of MEN and premature release of Cdc14 from the nucleolus, suggesting that this domain within Cdc15 functions to inhibit MEN signaling. Our findings indicate that multiple modes of MEN regulation occur through the protein kinase Cdc15.


2008 ◽  
Vol 32 (6) ◽  
pp. 862-869 ◽  
Author(s):  
Toshiya Tsuji ◽  
Eric Lau ◽  
Gary G. Chiang ◽  
Wei Jiang

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

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