I had an interesting issue lately with DPM 2012 R2 agents becoming unreachable on domain controllers. All other protected servers were unaffected.
I started with usual thins - checked the network connectivity and DNS, but everything seemed to be OK. Also I reinstalled the client on domain controllers, but the agent was still unreachable.
Finally it turned out that in the domain Builtin - Users group following members need to included: Domain Users, Authenticated Users and INTERACTIVE, in my case two of those were missing. I added them back, refreshed the agent status in DPM console and issue was resolved instantly.