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The histone chaperone complex FACT comprises SPT16 and SSRP1 and contributes to DNA replication, transcription, and repair, but how it plays such various roles is unclear. Here, we show that human SPT16 is ubiquitylated at lysine-674 (K674) by the DCAF14-CRL4 ubiquitin ligase. K674 is located in the middle domain of SPT16, and the corresponding residue of the yeast ortholog is critical for binding to histone H3.1-H4. We show that the middle domain of human SPT16 binds to histone H3.1-H4 and that this binding is inhibited by K674 ubiquitylation. Cells with heterozygous knockin of a K674R mutant of SPT16 manifest reduction of both SPT16 ubiquitylation and H3.1 in chromatin, a reduced population in mid S phase, impaired proliferation, and increased susceptibility to S phase stress. Our data thus indicate that SPT16 ubiquitylation by DCAF14-CRL4 regulates FACT binding to histones and may thereby control DNA replication-coupled histone incorporation into chromatin. [Display omitted] • The SPT16 subunit of the FACT complex is ubiquitylated at K674 • The ubiquitin ligase DCAF14-CRL4 is responsible for SPT16 ubiquitylation • Ubiquitylation of SPT16 inhibits its binding to histone H3.1 • SPT16 ubiquitylation increases the level of H3.1 in chromatin during S phase The histone chaperone FACT plays a role in DNA replication, transcription, and repair, but its regulation is unclear. Nakagawa et al. report that DCAF14-CRL4 ubiquitylates the FACT subunit SPT16 and that such ubiquitylation may regulate DNA replication-coupled histone incorporation into chromatin and thereby ensure efficient S-phase progression. [ABSTRACT FROM AUTHOR]