Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genomic integrity is maintained by checkpoints that guard against undesired replication after DNA damage. Here, we show that CDT1, a licensing factor of the pre-replication complex (preRC), is rapidly proteolysed after UV- or gamma-irradiation. The preRC assembles on replication origins at the end of mitosis and during G1 to license DNA for replication in S phase. Once the origin recognition complex (ORC) binds to origins, CDC6 and CDT1 associate with ORC and promote loading of the MCM2-7 proteins onto chromatin, generating the preRC. We show that radiation-mediated CDT1 proteolysis is independent of ATM and CHK2 and can occur in G1-phase cells. Loss of the COP9-signalosome (CSN) or CUL4-ROC1 complexes completely suppresses CDT1 proteolysis. CDT1 is specifically polyubiquitinated by CUL4 complexes and the interaction between CDT1 and CUL4 is regulated in part by gamma-irradiation. Our study reveals an evolutionarily conserved and uncharacterized G1 checkpoint that induces CDT1 proteolysis by the CUL4-ROC1 ubiquitin E3 ligase and CSN complexes in response to DNA damage.
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PMID:Radiation-mediated proteolysis of CDT1 by CUL4-ROC1 and CSN complexes constitutes a new checkpoint. 1457 10

The greatest difference between species is size; however, the developmental mechanisms determining organism growth remain poorly understood. Primordial dwarfism is a group of human single-gene disorders with extreme global growth failure (which includes Seckel syndrome, microcephalic osteodysplastic primordial dwarfism I [MOPD] types I and II, and Meier-Gorlin syndrome). Ten genes have now been identified for microcephalic primordial dwarfism, encoding proteins involved in fundamental cellular processes including genome replication (ORC1 [origin recognition complex 1], ORC4, ORC6, CDT1, and CDC6), DNA damage response (ATR [ataxia-telangiectasia and Rad3-related]), mRNA splicing (U4atac), and centrosome function (CEP152, PCNT, and CPAP). Here, we review the cellular and developmental mechanisms underlying the pathogenesis of these conditions and address whether further study of these genes could provide novel insight into the physiological regulation of organism growth.
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PMID:Mechanisms and pathways of growth failure in primordial dwarfism. 2197 14

Histone acetyltransferase binding to ORC-1 (HBO1) is a critically important histone acetyltransferase for forming the prereplicative complex (pre-RC) at the replication origin. Pre-RC formation is completed by loading of the MCM2-7 heterohexameric complex, which functions as a helicase in DNA replication. HBO1 recruited to the replication origin by CDT1 acetylates histone H4 to relax the chromatin conformation and facilitates loading of the MCM complex onto replication origins. However, the acetylation status and mechanism of regulation of histone H3 at replication origins remain elusive. HBO1 positively regulates cell proliferation under normal cell growth conditions. Whether HBO1 regulates proliferation in response to DNA damage is poorly understood. In this study, we demonstrated that HBO1 was degraded after DNA damage to suppress cell proliferation. Ser50 and Ser53 of HBO1 were phosphorylated in an ATM/ATR DNA damage sensor-dependent manner after UV treatment. ATM/ATR-dependently phosphorylated HBO1 preferentially interacted with DDB2 and was ubiquitylated by CRL4(DDB2). Replacement of endogenous HBO1 in Ser50/53Ala mutants maintained acetylation of histone H3K14 and impaired cell cycle regulation in response to UV irradiation. Our findings demonstrate that HBO1 is one of the targets in the DNA damage checkpoint. These results show that ubiquitin-dependent control of the HBO1 protein contributes to cell survival during UV irradiation.
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PMID:UV Damage-Induced Phosphorylation of HBO1 Triggers CRL4DDB2-Mediated Degradation To Regulate Cell Proliferation. 2954 85

Cardiomyopathy (CMP) is a group of myocardial diseases that progressively impair cardiac function. The mechanisms underlying CMP development are poorly understood, but lifestyle factors are clearly implicated as risk factors. This study aimed to identify molecular biomarkers involved in inflammatory CMP development and progression using a systems biology approach. The authors analysed microarray gene expression datasets from CMP and tissues affected by risk factors including smoking, ageing factors, high body fat, clinical depression status, insulin resistance, high dietary red meat intake, chronic alcohol consumption, obesity, high-calorie diet and high-fat diet. The authors identified differentially expressed genes (DEGs) from each dataset and compared those from CMP and risk factor datasets to identify common DEGs. Gene set enrichment analyses identified metabolic and signalling pathways, including MAPK, RAS signalling and cardiomyopathy pathways. Protein-protein interaction (PPI) network analysis identified protein subnetworks and ten hub proteins (CDK2, ATM, CDT1, NCOR2, HIST1H4A, HIST1H4B, HIST1H4C, HIST1H4D, HIST1H4E and HIST1H4L). Five transcription factors (FOXC1, GATA2, FOXL1, YY1, CREB1) and five miRNAs were also identified in CMP. Thus the authors' approach reveals candidate biomarkers that may enhance understanding of mechanisms underlying CMP and their link to risk factors. Such biomarkers may also be useful to develop new therapeutics for CMP.
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PMID:Network-based computational approach to identify genetic links between cardiomyopathy and its risk factors. 3219 66