Regulation of the Minichromosome Maintenance Protein 3 (MCM3) Chromatin Binding by the Prolyl Isomerase Pin1

2018 ◽  
Vol 430 (24) ◽  
pp. 5169-5181 ◽  
Author(s):  
Michael Schumann ◽  
Miroslav Malešević ◽  
Erik Hinze ◽  
Sebastian Mathea ◽  
Marat Meleshin ◽  
...  
Keyword(s):  
Chromatin Binding ◽  
Prolyl Isomerase ◽  
Minichromosome Maintenance ◽  
Minichromosome Maintenance Protein

scholarly journals Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ryan M. Baxley ◽  
Wendy Leung ◽  
Megan M. Schmit ◽  
Jacob Peter Matson ◽  
Lulu Yin ◽  
...  
Keyword(s):  
Immune Cell ◽  
Nk Cell ◽  
Restrictive Cardiomyopathy ◽  
Telomerase Activity ◽  
Compound Heterozygous ◽  
Minichromosome Maintenance ◽  
Telomere Shortening ◽  
Clinical Phenotypes ◽  
Eukaryotic Dna ◽  
Minichromosome Maintenance Protein

AbstractMinichromosome maintenance protein 10 (MCM10) is essential for eukaryotic DNA replication. Here, we describe compound heterozygous MCM10 variants in patients with distinctive, but overlapping, clinical phenotypes: natural killer (NK) cell deficiency (NKD) and restrictive cardiomyopathy (RCM) with hypoplasia of the spleen and thymus. To understand the mechanism of MCM10-associated disease, we modeled these variants in human cell lines. MCM10 deficiency causes chronic replication stress that reduces cell viability due to increased genomic instability and telomere erosion. Our data suggest that loss of MCM10 function constrains telomerase activity by accumulating abnormal replication fork structures enriched with single-stranded DNA. Terminally-arrested replication forks in MCM10-deficient cells require endonucleolytic processing by MUS81, as MCM10:MUS81 double mutants display decreased viability and accelerated telomere shortening. We propose that these bi-allelic variants in MCM10 predispose specific cardiac and immune cell lineages to prematurely arrest during differentiation, causing the clinical phenotypes observed in both NKD and RCM patients.

scholarly journals Regulation of Replication Licensing by Acetyltransferase Hbo1

2006 ◽  
Vol 26 (3) ◽  
pp. 1098-1108 ◽  
Author(s):  
Masayoshi Iizuka ◽  
Tomoko Matsui ◽  
Haruhiko Takisawa ◽  
M. Mitchell Smith
Keyword(s):  
Dna Replication ◽  
Origin Recognition Complex ◽  
Cyclin Dependent Kinase ◽  
Chromatin Binding ◽  
Regulatory Factor ◽  
Minichromosome Maintenance ◽  
Egg Extracts ◽  
Sequential Binding ◽  
Initiation Of Dna Replication ◽  
Prereplicative Complex

ABSTRACT The initiation of DNA replication is tightly regulated in eukaryotic cells to ensure that the genome is precisely duplicated once and only once per cell cycle. This is accomplished by controlling the assembly of a prereplicative complex (pre-RC) which involves the sequential binding to replication origins of the origin recognition complex (ORC), Cdc6/Cdc18, Cdt1, and the minichromosome maintenance complex (Mcm2-Mcm7, or Mcm2-7). Several mechanisms of pre-RC regulation are known, including ATP utilization, cyclin-dependent kinase levels, protein turnover, and Cdt1 binding by geminin. Histone acetylation may also affect the initiation of DNA replication, but at present neither the enzymes nor the steps involved are known. Here, we show that Hbo1, a member of the MYST histone acetyltransferase family, is a previously unrecognized positive regulatory factor for pre-RC assembly. When Hbo1 expression was inhibited in human cells, Mcm2-7 failed to associate with chromatin even though ORC and Cdc6 loading was normal. When Xenopus egg extracts were immunodepleted of Xenopus Hbo1 (XHbo1), chromatin binding of Mcm2-7 was lost, and DNA replication was abolished. The binding of Mcm2-7 to chromatin in XHbo1-depleted extracts could be restored by the addition of recombinant Cdt1.

scholarly journals Hippocampal Proliferation Is Increased in Presymptomatic Parkinson’s Disease and due to Microglia

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Karlijn J. Doorn ◽  
Benjamin Drukarch ◽  
Anne-Marie van Dam ◽  
Paul J. Lucassen
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Subventricular Zone ◽  
Lewy Body Disease ◽  
Minichromosome Maintenance ◽  
Proliferating Cells ◽  
Cognitive Changes ◽  
Incidental Lewy Body Disease ◽  
Minichromosome Maintenance Protein ◽  
Microglial Response

Besides dopamine-deficiency related motor symptoms, nonmotor symptoms, including cognitive changes occur in Parkinson's disease (PD) patients, that may relate to accumulation ofα-synuclein in the hippocampus (HC). This brain region also contains stem cells that can proliferate. This is a well-regulated process that can, for example, be altered by neurodegenerative conditions. In contrast to proliferation in the substantia nigra and subventricular zone, little is known about the HC in PD. In addition, glial cells contribute to neurodegenerative processes and may proliferate in response to PD pathology. In the present study, we questioned whether microglial cells proliferate in the HC of established PD patients versus control subjects or incidental Lewy body disease (iLBD) cases as a prodromal state of PD. To this end, proliferation was assessed using the immunocytochemical marker minichromosome maintenance protein 2 (MCM2). Colocalization with Iba1 was performed to determine microglial proliferation. MCM2-positive cells were present in the HC of controls and were significantly increased in the presymptomatic iLBD cases, but not in established PD patients. Microglia represented the majority of the proliferating cells in the HC. This suggests an early microglial response to developing PD pathology in the HC and further indicates that neuroinflammatory processes play an important role in the development of PD pathology.

scholarly journals MCM7 Ubiquitination Regulates CMG Helicase Disassembly in Human

2021 ◽  
Author(s):  
Qianqian Sun ◽  
Kun Liu ◽  
Fangzhou Li ◽  
Bingquan Qiu ◽  
Zhisong Fu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Genome Stability ◽  
Human Tumor ◽  
Cell Fractionation ◽  
Minichromosome Maintenance ◽  
E3 Ligases ◽  
Minichromosome Maintenance Protein ◽  
Fork Stalling

Abstract BackgroundThe disassembly of the replisome plays an essential role in maintaining genome stability at the termination of DNA replication. However, the mechanism of replisome disassembly remains unknown in human. In this study, we screened E3 ligases and deubiquitinases (DUBs) for the ubiquitination of minichromosome maintenance protein (MCM) 7 and provided evidence of this process driving CMG helicase disassembly in human tumor cells. MethodsSILAC-MS/MS was analyzed to identify ubiquitinated proteins in HeLa cells. The ubiquitination/deubiquitylation assay in vitro and in vivo were detected by Western blot. Thymidine and HU were implied to synchronized cell cycle，and detect the role of ubiquitinated MCM7 in cell cycle. Cell fractionation assay was used to detect the function of ubiquitination of MCM7 in chromatin and non-chromatin. Aphidicolin、Etoposide、ICRF-193 and IR were applied to cause replication fork stalling. MG-132 and NMS-873 were used to inhibit the proteasome degradation and p97 segregase. Flow cytometer and FlowJo flow cytometry software were used to cell cycle analysis.ResultsIn our study, we found that the ubiquitin ligase RNF8 catalyzes the k63-linked poly-ubiquitination of MCM7 both in vivo and in vitro, and lysine 145 of MCM7 is the primary ubiquitination site. Moreover, the poly-ubiquitination of MCM7 mainly exists in the chromatin, which is dynamically regulated by the cell cycle, mainly occurs in the late S phase. And DNA damage can significantly reduce the poly-ubiquitylation of MCM7 in the late S phage. Furthermore, the proteasome, p97 segregase, USP29 and ATXN3 are required for the removal of MCM7 ubiquitination to promote the disassembly of CMG on chromatin. ConclusionsIn the late S phage of cell cycle, RNF8 catalyzes the poly-ubiquitination of MCM7, and then initiates the disassembly of CMG helicase from chromatin, which is mediated by p97, proteasome, USP29 and ATXN3 in human. We reveal the novel function of the poly-ubiquitylation of MCM7, which is a regulatory signal to control CMG complex unloading at replication termination sites.

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