The CCAAT box is a DNA element present in the majority of human promoters, bound 
by the trimeric NF-Y, composed of NF-YA, NF-YB, and NF-YC subunits. We describe 
and characterize novel isoforms of one of the two histone-like subunits, NF-YC. 
The locus generates a minimum of four splicing products, mainly located within 
the Q-rich activation domain. The abundance of each isoform is cell-dependent; 
only one major NF-YC isoform is present in a given cell type. The 37- and 50-kDa 
isoforms are mutually exclusive, and preferential pairings with NF-YA isoforms 
possess different transcriptional activities, with specific combinations being 
more active on selected promoters. The transcriptional regulation of the NF-YC 
locus is also complex, and mRNAs arise from the two promoters P1 and P2. 
Transient transfections, chromatin immunoprecipitations, and reverse 
transcription-PCRs indicate that P1 has a robust housekeeping activity; P2 
possesses a lower basal activity, but it is induced in response to DNA damage in 
a p53-dependent way. Alternative promoter usage directly affects NF-YC splicing, 
with the 50-kDa transcript being excluded from P2. Specific functional 
inactivation of the 37-kDa isoform affects the basal levels of G(1)/S blocking 
and pro-apoptotic genes but not G(2)/M promoters. In summary, our data highlight 
an unexpected degree of complexity and regulation of the NF-YC gene, 
demonstrating the existence of a discrete cohort of NF-Y trimer subtypes 
resulting from the functional diversification of Q-rich transactivating subunits 
and a specific role of the 37-kDa isoform in suppression of the DNA 
damage-response under growing conditions.