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Shortage of dNTPs underlies replication defects and genome instability in the absence of the APC/C cofactor Cdh1

AutorGarzón, Javier ; Moreno, Sergio; García-Higuera, Irene
Fecha de publicación2016
CitaciónXXXIX Congreso de la SEBBM (2016)
ResumenThe anaphase promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that promotes proteasomal degradation of mitotic cyclins and other critical cell-cycle regulators. Its activity is limited to the cell cycle period comprised between anaphase and the end of the G1 phase, and is controlled by the regulated binding of two co-factors: Cdc20 or Cdh1. APC/C-Cdc20 is active during anaphase, while APC/C-Cdh1 is active from anaphase until the end of G1.Over the last few years, our group has been addressing the biological function of the APC/C-Cdh1 complex using mouse models of Cdh1 deficiency. Cells derived from mutant embryos (MEFs) accumulate DNA breaks and show increased levels of RPA foci and phospho-Chk1, suggestive of replication stress. Direct analysis of the DNA replication process on stretched DNA fibers (DNA fiber assays) revealed reduced rates of replication fork progression and increased frequency of origin firing in the absence of Cdh1. Interestingly, addition of exogenous dNTPs or nucleosides, normalized replication dynamics in mutant cells, and prevented DNA breakage. Consistently, quantification of intracellular dNTP pools confirmed decreased levels of all four dNTPs in Cdh1-deficient MEFs. Moreover, overexpression of RRM2, the regulatory subunit of Ribonucleotide Reductase (the rate-limiting enzyme for dNTP synthesis), restored efficient replication and genome stability in cells lacking Cdh1 expression. These results highlight the importance of APC/C activity during the G1 phase to prevent replication defects, and provide evidence that, in the absence of Cdh1, insufficient supply of dNTPs to the replisome leads to replication stress, which, in turn, causes chromosomal breaks.
DescripciónResumen del póster presentado al XXXIX Congreso de la Sociedad Española de Bioquímica y Biología Molecular, celebrado en Salamanca del 5 al 8 de septiembre de 2016.
Aparece en las colecciones: (IBFG) Comunicaciones congresos
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