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Molecular and Cellular Biology, November 2007, p. 7828-7838, Vol. 27, No. 22
0270-7306/07/$08.00+0     doi:10.1128/MCB.01276-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Unstable Spinocerebellar Ataxia Type 10 (ATTCT)·(AGAAT) Repeats Are Associated with Aberrant Replication at the ATX10 Locus and Replication Origin-Dependent Expansion at an Ectopic Site in Human Cells{triangledown}

Guoqi Liu,1 John J. Bissler,2 Richard R. Sinden,3 and Michael Leffak1*

Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, Ohio 45435,1 Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45220,2 Department of Biological Sciences, Florida Institute of Technology, Melbourne, Florida 329013

Received 16 July 2007/ Returned for modification 9 August 2007/ Accepted 30 August 2007

Spinocerebellar ataxia type 10 (SCA10) is associated with expansion of (ATTCT)n repeats (where n is the number of repeats) within the ataxin 10 (ATX10/E46L) gene. The demonstration that (ATTCT)n tracts can act as DNA unwinding elements (DUEs) in vitro has suggested that aberrant replication origin activity occurs at expanded (ATTCT)n tracts and may lead to their instability. Here, we confirm these predictions. The wild-type ATX10 locus displays inefficient origin activity, but origin activity is elevated at the expanded ATX10 loci in patient-derived cells. To test whether (ATTCT)n tracts can potentiate origin activity, cell lines were constructed that contain ectopic copies of the c-myc replicator in which the essential DUE was replaced by ATX10 DUEs with (ATTCT)n. ATX10 DUEs containing (ATTCT)27 or (ATTCT)48, but not (ATTCT)8 or (ATTCT)13, could substitute functionally for the c-myc DUE, but (ATTCT)48 could not act as an autonomous replicator. Significantly, chimeric c-myc replicators containing ATX10 DUEs displayed length-dependent (ATTCT)n instability. By 250 population doublings, dramatic two- and fourfold length expansions were observed for (ATTCT)27 and (ATTCT)48 but not for (ATTCT)8 or (ATTCT)13. These results implicate replication origin activity as one molecular mechanism associated with the instability of (ATTCT)n tracts that are longer than normal length.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435. Phone: (937) 775-3125. Fax: (937) 775-3730. E-mail: michael.leffak{at}wright.edu

{triangledown} Published ahead of print on 10 September 2007.

Molecular and Cellular Biology, November 2007, p. 7828-7838, Vol. 27, No. 22
0270-7306/07/$08.00+0     doi:10.1128/MCB.01276-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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