Nuclear DNA is packaged into nucleosomes by histone proteins to create chromatin. The assembly of chromatin is not a passive process but requires the activity of a network of histone-chaperone proteins that facilitate histone stability, prevent aggregation, organize histone transport and facilitate their deposition. Histone chaperones must deal with new histones, and also with pre-existing histones that are evicted from chromatin. DNA replication, DNA transcription and access to other control elements in the genome require nucleosomes be either moved out of the way (slid) or removed, resulting in the eviction of pre-existing histones. Specific chaperones contribute to the selective timing and placement of histone H3 variant deposition. However, many histone chaperones are agnostic about the variant or modification status of the histones they bind. Very little information exists as to how the chaperone pathways for new and pre-existing histone differ. NASP has long been appreciated as a key histone chaperone for histone H3 and histone H4, that functions irrespective of histone variant or posttranslational modification. NASP also binds the histone acetyltransferase enzyme HAT1 which contribute to the acetylation of new H4 histones at K12. Aim1 of this application will define novel interactions of NASP during DNA synthesis that contribute to new histone supply. Our work will also take an unbiased approach to ordering the process of histone-chaperone interaction during new histone deposition and histone eviction. A novel chaperone pathway for pre-existing nucleosomes that have been evicted from chromatin will be defined in aim 2 of the proposal. Finally, Aim 3 will define a novel mechanism for crosstalk between histone supply and nucleotide metabolism. Our work proposed in this application will define, for the first time, differential processes that regulate fate of new and pre-existing histones and provide a new paradigm for coordinated metabolic control.
|Effective start/end date||8/1/21 → 6/30/25|
- National Institute of General Medical Sciences (5R01GM143638-03)
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