Mutations in pericentrin cause Seckel syndrome with defective ATR-dependent DNA damage signaling

Medical Research Council (MRC) Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
Nature Genetics (Impact Factor: 29.65). 03/2008; 40(2):232-6. DOI: 10.1038/ng.2007.80
Source: PubMed

ABSTRACT Large brain size is one of the defining characteristics of modern humans. Seckel syndrome (MIM 210600), a disorder of markedly reduced brain and body size, is associated with defective ATR-dependent DNA damage signaling. Only a single hypomorphic mutation of ATR has been identified in this genetically heterogeneous condition. We now report that mutations in the gene encoding pericentrin (PCNT)--resulting in the loss of pericentrin from the centrosome, where it has key functions anchoring both structural and regulatory proteins--also cause Seckel syndrome. Furthermore, we find that cells of individuals with Seckel syndrome due to mutations in PCNT (PCNT-Seckel) have defects in ATR-dependent checkpoint signaling, providing the first evidence linking a structural centrosomal protein with DNA damage signaling. These findings also suggest that other known microcephaly genes implicated in either DNA repair responses or centrosomal function may act in common developmental pathways determining human brain and body size.

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Available from: Sarah Walker, Jul 09, 2015
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    • "Modeling experiments in Xenopus egg extracts now bring these diverse threads together into a coherent reiteration of the fission yeast data by supporting the concept of waves of Cdk1/cyclin B feedback loop activities emanating from the centrosome (Chang and Ferrell 2013). A final twist to centrosomal control has been provided by the demonstration that pericentrin mutations alter the DNA damage checkpoint response (Griffith et al. 2008). This link had been anticipated by reports that centrosomal Chk1 played a critical role in determining the timing of mitotic commitment. "
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    • "In conclusion, out data establishes Ccdc13 as a novel centrosomal satellite protein which joins an increasing number of human centrosomal proteins including Cep63, Cep131, Cep152, Cep164 and pericentrin that are important for maintaining genome stability (Griffith et al., 2008; Kalay et al., 2011; Sivasubramaniam et al., 2008; Smith et al., 2009; Staples et al., 2012). "
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    • "Currently, mutations in genes encoding core centrosome and centrosome-associated proteins represent the most frequent causative defect identified so far in MPDs. the centrosome is an important microtubule-organizing centre essential for coordinating G2-M progression, normal mitotic cell division and even cilia formation. Interestingly, defects in the atr-dependent DDr and in Dna replication licensing machinery are also associated with centrosome abnormalities, and vice versa, suggestive of a multifactorial but interconnected underlying pathobiology of MPDs (alderton et al. 2004, 2006; Griffith et al. 2008; stiff et al. 2013). the centromeric kinetochore of mitotic chromosomes is the attachment site for spindle microtubules, ensuring their amphitelic attachments onto all of the chromosomes, thereby enabling their alignment at metaphase (Hori and Fukagawa 2012; santaguida and Musacchio 2009). "
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