Whether or not proteins used within the nucleus itself are synthesized on the rough ER is part of an advanced sub-set of questions that could find their way onto the MCAT. The use of signal sequences in protein targeting is an important topic. Although the outer nuclear membrane is continuous with the endoplasmic reticulum (in fact, following cell division, the ER gives rise to the new nuclear membrane), all proteins utilized within the nucleus are synthesized on free ribosomes in the cytosol. These proteins cross the nuclear membrane through nuclear pores. Short peptide signals, called nuclear localization signals, direct these proteins, such as DNA polymerases and RNA polymerases, into the nucleus. This is a similar mechanism to the signal sequences that direct proteins to be sorted, modified, and/or secreted by the cell to the rough ER. In other words, not all signal sequences lead to the rough ER.