American uncle on huge island (5)
I believe the answer is:
samos
'island' is the definition.
(Samos is a Greek island)
'american uncle on huge' is the wordplay.
'american uncle' becomes 'Sam' (Uncle Sam is a nickname for the USA).
'on' means one lot of letters go next to another (in a down clue, letters appear on others).
'huge' becomes 'os' (abbreviation for outsize).
'sam'+'os'='SAMOS'
(Other definitions for samos that I've seen before include "Aegean Sea island" , "birthplace of Pythagoras" , "Greek island?" , "somewhere in the Aegean" .)