You need to keep your users happy - if they need to upload 16MB+ files, then that's what you have to enable. Talk to them and establish a rough limit if you can, they'll have the best idea of the file sizes involved - try to stick to the smallest, practical value, don't just go straight to 300MB or more. Don't allow multiple uploads in one go either, if you can.
If you only enable uploads from certain pages, you can use a <location> element in your Web.config to increase the upload limit just for those pages / directories, rather than for the entire site - while it wouldn't prevent a DOS attack, it reduces the surface area over which such an attack would be most viable, although you're highly unlikely to encounter such an attack anyway.
eg:
<location path="Upload.aspx">
<system.web>
<httpRuntime maxRequestLength="16384" /> <!-- 16MB -->
</system.web>
</location>