There are several reports that demonstrate roles

There are several reports that demonstrate roles for Rad51 in addition to its participation in classical HR-mediated DSB repair. For example, in Saccharomyces cerevisiae that lack telomerase or certain telomere binding proteins, the telomeres can be maintained in rare survivors by alternative recombination events dependent on either Rad50 (type II) or Rad51(type I) (Grandin and Charbonneau, 2003; Le et al., 1999; Lin et al., 2009). In mammalian cells, an association between Rad51 and telomeres at the late S and G2 phases of the purchase VX-765 has been described, and has been proposed to aid in the formation of the t-loop (Verdun and Karlseder, 2006). Additionally, a recent report has shown that knockdown of Rad51 protein with shRNA in p53 deficient MEFs or in MEFs with a conditional loss of BRCA2, which is responsible for loading Rad51 onto DNA, resulted in significant erosion of telomeres compared with wildtype cells (Badie et al., 2010). The tight regulation of Rad51 and consequent HR at telomeres, however, is essential for the prevention of chromosomal aberrations stemming from telomere sister chromatid exchanges that are attributed to inappropriate recombination (Gauthier et al., 2012). While it is possible that the Rad51 foci in unchallenged ES cells are associated with telomeres, the fact that many of these Rad51 foci also co‐localize with γ-H2AX would suggest that the telomeres are damaged, since γ-H2AX is also used as a marker of uncapped or damaged telomeres (Hao et al., 2004; Nakamura et al., 2009). In addition to its roles in telomere maintenance and replication, Rad51 can physically associate with mitochondrial DNA (mtDNA), and in conjunction with other Rad51 family members Rad51C and XRCC3, is critical for maintaining proper mtDNA copy number (Sage et al., 2010). However, ES cells have few mitochondria per cell (Saretzki et al., 2008), and all of the detectable Rad51 observed by immunofluorescence is localized in the nucleus, suggesting that the predominant role of the elevated Rad51 protein expression in these cells is to participate in DNA DSB repair and/or other potential nuclear functions. The following are the supplementary materials related to this article.
Conflict of interest
Acknowledgments We thank Drs. Robert Holdcraft and David Myer for assistance with experimental design and technical assistance. This work was supported in part by grants R01 ES012695 and R01 ES12695-4S1 to PJS from the National Institutes of Health and the Center for Environmental Genetics, P30 ES006096, and by NIH grants ES011633 and P30 ES005022 to JAT. EDT was supported by an NIH training grantT32 ES007250.
Introduction Huntington\'s disease (HD) is a progressive, fatal and neurodegenerative disorder produced by CAG trinucleotide expansion in exon 1 of the gene coding for the huntingtin protein (htt) (The Huntington\'s Disease Collaborative Research Group, 1993). Despite the widespread expression of htt in the brain and the body, expression of mutant htt leads to the selective death of the medium-size spiny GABAergic neurons in the striatum (Cowan and Raymond, 2006; Sieradzan and Mann, 2001; Subramaniam et al., 2009), resulting in the appearance of generalized involuntary movements. Excitotoxicity is suggested to be involved in the pathogenesis of HD and intrastriatal injection of quinolinic acid (QUIN), an agonist of the N-methyl-d-aspartic acid receptor, induces a similar pattern of neuronal death (Estrada Sanchez et al., 2008). MSC transplantation has been found to produce improvements in several disease neurodegenerative models, including Alzheimer\'s disease (Lee et al., 2010), amyotrophic lateral sclerosis (Kassis et al., 2008) and acid sphingomyelinase deficiency (Jin et al., 2002). MSC-mediated neuroprotection is often associated with their anti-inflammatory effects (Ohtaki et al., 2008) and/or secretion of growth factors (Caplan and Dennis, 2006), which might serve to inhibit disease progression (Le Blanc and Ringden, 2007; Uccelli et al., 2007). The neuroprotective properties of MSC raise the possibility of developing a therapy to prevent or retard the degeneration of vulnerable striatal neuronal populations in HD, which could be a more feasible approach than neuronal replacement in a clinical scenario.