Minichromosome Maintenance Protein 6 (MCM 6) Expression im Kolorektalen Karzinom: Ein Proliferationsmarker und neuer Prognosefaktor

2011 ◽  
Vol 49 (08) ◽  
Author(s):  
C Schrader ◽  
F Gieseler ◽  
J Bräsen ◽  
S Nazzal ◽  
B Sipos ◽  
...  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ryan M. Baxley ◽  
Wendy Leung ◽  
Megan M. Schmit ◽  
Jacob Peter Matson ◽  
Lulu Yin ◽  
...  

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.


2018 ◽  
Vol 430 (24) ◽  
pp. 5169-5181 ◽  
Author(s):  
Michael Schumann ◽  
Miroslav Malešević ◽  
Erik Hinze ◽  
Sebastian Mathea ◽  
Marat Meleshin ◽  
...  

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Karlijn J. Doorn ◽  
Benjamin Drukarch ◽  
Anne-Marie van Dam ◽  
Paul J. Lucassen

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.


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