Correction of double strand DNA breaks proceeds in an error-free pathway of 
homologous recombination (HR), which can result in gene silencing of half of the 
DNA molecules caused by action by DNA methyltransferase 1 (DNMT1) (Cuozzo, C., 
Porcellini, A., Angrisano, T., Morano, A., Lee, B., Di Pardo, A., Messina, S., 
Iuliano, R., Fusco, A., Santillo, M. R., Muller, M. T., Chiariotti, L., 
Gottesman, M. E., and Avvedimento, E. V. (2007) PLoS Genet. 3, e110). To explore 
the mechanism that leads to HR-induced silencing, a genetic screen was carried 
out based on the silencing of a GFP reporter to identify potential partners. 
DMAP1, a DNMT1 interacting protein, was identified as a mediator of this 
process. DMAP1 is a potent activator of DNMT1 methylation in vitro, suggesting 
that DMAP1 is a co-repressor that supports the maintenance and de novo action of 
DNMT1. To examine critical roles for DMAP1 in vivo, lentiviral shRNA was used to 
conditionally reduce cellular DMAP1 levels. The shRNA transduced cells grew 
poorly and eventually ceased their growth. Analysis of the tumor suppressor gene 
p16 methylation status revealed a clear reduction in methylated CpGs in the 
shRNA cells, suggesting that reactivation of a tumor suppressor gene pathway 
caused the slow growth phenotype. Analysis of HR, using a fluorescence-based 
reporter, revealed that knocking down DMAP1 also caused hypomethylation of the 
DNA repair products following gene conversion. DMAP1 was selectively enriched in 
recombinant GFP chromatin based on chromatin immunoprecipitation analysis. The 
picture that emerges is that DMAP1 activates DNMT1 preferentially at sites of HR 
repair. Because DMAP1 depleted cells display enhanced HR, we conclude that it 
has additional roles in genomic stability.