The ATTCT repeats of spinocerebellar ataxia type 10 display strong nucleosome assembly which is enhanced by repeat interruptions.
Nucleosome packaging influences many aspects of DNA metabolism such as replication, repair and transcription, and via this link likely has further downstream effects on genome stability. The instability and expansion of repetitive sequences is associated with at least 42 human diseases, yet the molecular conditions contributing to repeat instability have remained largely undetermined. Previously we showed strong nucleosome formation on CAG repeats associated with spinocerebellar ataxia type 1 and very weak formation on CGG repeats associated with fragile X syndrome, and that interruption of these repeat tracts made the DNA behave more like random sequences. In this study, we determined nucleosome formation on pure and interrupted ATTCT pentanucleotides associated with spinocerebellar ataxia type 10 (SCA10). We report strong nucleosome formation on ATTCT repeats, like CAG tracts. Surprisingly, in contrast to the effect of interruptions on other repeat sequences, interruptions in the expanded ATTCT tracts further strengthened assembly with hyperacetylated histones under physiological conditions with NAP-1. These differences may contribute to phenotypic variation seen between families having pure and interrupted SCA10 repeats, as well as the overall genetic instability at the SCA10 locus.
Hagerman
Katharine A
KA
Program of Genetics and Genome Biology, the Hospital for Sick Children, Toronto, ON, Canada M5G 1X8.
Ruan
Haihe
H
Edamura
Kerrie Nichol
KN
Matsuura
Tohru
T
Pearson
Christopher E
CE
Wang
Yuh-Hwa
YH
D000107:Acetylation; D000067736:Ataxin-10; D001483:Base Sequence; D045584:Chromosome Positioning; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009707:Nucleosomes / Q000235:genetics*; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics*; D020754:Spinocerebellar Ataxias / Q000235:genetics*
C503889:ATXN10 protein, human; D000067736:Ataxin-10; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009707:Nucleosomes