Cross-linking and immunoprecipitation (CLIP) is increasingly used to map 
transcriptome-wide binding sites of RNA-binding proteins. We developed a method 
for CLIP data analysis, and applied it to compare CLIP with photoactivatable 
ribonucleoside-enhanced CLIP (PAR-CLIP) and to uncover how differences in 
cross-linking and ribonuclease digestion affect the identified sites. We found 
only small differences in accuracies of these methods in identifying binding 
sites of HuR, which binds low-complexity sequences, and Argonaute 2, which has a 
complex binding specificity. We found that cross-link-induced mutations led to 
single-nucleotide resolution for both PAR-CLIP and CLIP. Our results confirm the 
expectation from original CLIP publications that RNA-binding proteins do not 
protect their binding sites sufficiently under the denaturing conditions used 
during the CLIP procedure, and we show that extensive digestion with 
sequence-specific RNases strongly biases the recovered binding sites. This bias 
can be substantially reduced by milder nuclease digestion conditions.