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Expansion of CAG triplet repeats by human DNA polymerases lambda and beta in vitro, is regulated by flap endonuclease 1 and DNA ligase 1.

Autori

Crespan E, Hubscher U, Maga G.

Riferimenti

DNA REPAIR 29 101-111, 2015

Autori CNR

CRESPAN, MAGA

Moduli

Abstract

Huntington's disease (HD) is a neurological genetic disorder caused by the expansion of the CAG trinucleotide repeats (TNR) in the N-terminal region of coding sequence of the Huntingtin's (HTT) gene. This results in the addition of a poly-glutamine tract within the Huntingtin protein, resulting in its pathological form. The mechanism by which TRN expansion takes place is not yet fully understood. We have recently shown that DNA polymerase (Pol) beta can promote the microhomology-mediated end joining andtriplet expansion of a substrate mimicking a double strand break in the TNR region of the HTT gene. Here we show that TNRexpansion is dependent on the structure of the DNA substrate, as well as on the two essential Pol beta co-factors: flap endonuclease1 (Fen1) and DNA ligase 1 (Lig1). We found that Fen1 significantly stimulated TNR expansion by Pol beta, but not by the related enzyme Pol lambda, and subsequent ligation of the DNA products by Lig1. Interestingly, the deletion of N-terminal domains of Pol lambda, resulted in an enzyme which displayed properties more similar to Pol beta, suggesting a possible evolutionary mechanism. These results may suggest a novel mechanism for somatic TNR expansion in HD.

Link all articolo

http://www.sciencedirect.com/science/article/pii/S1568786415000178

Parole Chiave

Note

Indietro


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