ATM and ATR protect the genome against two different types of tandem repeat instability in Fragile X premutation mice

Abstract

Expansion of a tandem repeat tract is responsible for the Repeat Expansion diseases, a group of more than 20 human genetic disorders that includes those like Fragile X (FX) syndrome that result from repeat expansion in the FMR1 gene. We have previously shown that the ATM and Rad3-related (ATR) checkpoint kinase protects the genome against one type of repeat expansion in a FX premutation mouse model. By crossing the FX premutation mice to Ataxia Telangiectasia-Mutated (Atm) mutant mice, we show here that ATM also prevents repeat expansion. However, our data suggest that the ATM-sensitive mechanism is different from the ATR-sensitive one. Specifically, the effect of the ATM deficiency is more marked when the premutation allele is paternally transmitted and expansions occur more frequently in male offspring regardless of the Atm genotype of the offspring. The gender effect is most consistent with a repair event occurring in the early embryo that is more efficient in females, perhaps as a result of the action of an X-linked DNA repair gene. Our data thus support the hypothesis that two different mechanisms of FX repeat expansion exist, an ATR-sensitive mechanism seen on maternal transmission and an ATM-sensitive mechanism that shows a male expansion bias.

Mouse Models of the Fragile X Premutation and the Fragile X Associated Tremor/Ataxia Syndrome

“…This model also shows a trend toward gradual increases in CGG (or CGG-CCG) repeat lengths. Furthermore, the CGG-CCG mice show the same general pattern of repeat instability as that reported in the PM, namely that the paternal mutation shows small repeat expansions, and this expansion occurs preferentially in mice lacking ATM, with a bias toward greater expansions in males (Entezam and Usdin 2008, 2009). …”

Contracting CAG/CTG repeats using the CRISPR-Cas9 nickase

“…Atm +/− animals, by contrast, did not display an overt somatic instability phenotype. Instead, they showed markedly increased frequencies of expansions in the male germlines58. The effect on contractions was not reported.…”

Stabilization of histone demethylase PHF8 by USP7 promotes breast carcinogenesis

“…The functional involvement of PHF8 in DDR is especially appealing given that genomic instability is disclosed as a common feature in fragile X syndrome (60,61) and PHF8 truncations (62) or mutations (62) are linked to intellectual disability. It is tempting to speculate that the role of PHF8 in DDR might represent a novel, previously unappreciated contributing factor in the development of fragile X syndrome, the understanding of which will broaden the insight into the regulation of genome/epigenome integrity and the pathogenesis of neurological diseases.…”