Chromatin assembly factor 1

Chromatin assembly factor-1 (CAF-1) is a protein complex — including Chaf1a (p150),  Chaf1b (p60), and p48 subunits in humans, or Cac1, Cac2, and Cac3, respectively, in yeast— that assembles histone tetramers onto replicating DNA during the S phase of the cell cycle.[1][2][3][4]

Steps in nucleosome assembly. CAF-1 is shown in yellow interacting with the H3-H4 tetramer.

Function

CAF-1 functions as a histone chaperone that mediates the first step in nucleosome formation by tetramerizing and depositing newly synthesized histone H3/H4 onto DNA rapidly behind replication forks.[5][6][7] H3 and H4 are synthesized in the cytoplasm.[4] Several studies have shown that the interaction between CAF-1 and PCNA (proliferating cell nuclear antigen, which stabilizes CAF-1 at replication forks, is important for CAF-1's role in nucleosome assembly[8]

The three subunits work together to make the complex function. The human subunit (p150) interacts with PCNA, which acts as a sliding clamp, to help the CAF-1 complex interact with the DNA replication fork. Additionally, p150 along with PCNA performs nucleotide excision repair to fix any damaged DNA. P60 interacts with ASF1a/b, which is a histone chaperone for H3/H4. p48 has roles outside of CAF-1, but when involved with the complex, it binds to H4.[4]

p60 attracts ASF1a/b which is a chaperone for H3/H4 and this is in the complex with p150 which interacts with PCNA to attach to the replication fork. The CAF-1 complex adds the histones to the DNA ahead of the replication fork.[4]

A mutation in p150 that results in a loss of function would lead to double stranded breaks, interruptions in the replication fork and translocations. In p60, loss of function would mean the histone chaperone for H3/H4 would not interact with the complex. A mutation like this in either subunit would result in loss of function for the CAF-1 complex as a whole. However, loss of function in p48 would alter how well the complex is able to chaperone chromatin, but would not stop it as a whole.[4]

Roles

CAF-1 is required for the spatial organization and epigenetic marking of heterochromatin domains in pluripotent embryonic cells, creating a cellular memory of somatic cell identity during cellular differentiation.[9]

Cells resembling 2-cell-stage mouse embryos (totipotent cells) can be induced in vitro through downregulation of the chromatin-assembly activity of CAF-1 in embryonic stem cells.[10]

CAF-1 forms a deadenylase complex with CCR4-Not, which should not be confused with the unrelated CCR4. The CAF-1/CCR4-Not complex cooperates with the release factor eRF3 and PABPC1 to shorten the poly(A) tail of mRNA during translation.[11]

References
  1. Fang, Dong; Han, Junhong (2020-11-06). Histone Mutations and Cancer. Springer Nature. ISBN 978-981-15-8104-5.
  2. Smith S, Stillman B (July 1989). "Purification and characterization of CAF-I, a human cell factor required for chromatin assembly during DNA replication in vitro". Cell. 58 (1): 15–25. doi:10.1016/0092-8674(89)90398-X. PMID 2546672. S2CID 10515064.
  3. Hoek M, Stillman B (October 2003). "Chromatin assembly factor 1 is essential and couples chromatin assembly to DNA replication in vivo". Proceedings of the National Academy of Sciences of the United States of America. 100 (21): 12183–12188. Bibcode:2003PNAS..10012183H. doi:10.1073/pnas.1635158100. PMC 218733. PMID 14519857.
  4. Volk, Andrew; Crispino, John D. (August 2015). "The role of the chromatin assembly complex (CAF-1) and its p60 subunit (CHAF1b) in homeostasis and disease". Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms. 1849 (8): 979–986. doi:10.1016/j.bbagrm.2015.05.009. ISSN 0006-3002. PMC 4515380. PMID 26066981.
  5. Liu WH, Roemer SC, Zhou Y, Shen ZJ, Dennehey BK, Balsbaugh JL, et al. (September 2016). "The Cac1 subunit of histone chaperone CAF-1 organizes CAF-1-H3/H4 architecture and tetramerizes histones". eLife. 5: e18023. doi:10.7554/eLife.18023. PMC 5045291. PMID 27690308.
  6. Sauer PV, Timm J, Liu D, Sitbon D, Boeri-Erba E, Velours C, et al. (March 2017). "Insights into the molecular architecture and histone H3-H4 deposition mechanism of yeast Chromatin assembly factor 1". eLife. 6: e23474. doi:10.7554/elife.23474. PMC 5404918. PMID 28315525.
  7. Mattiroli F, Gu Y, Yadav T, Balsbaugh JL, Harris MR, Findlay ES, et al. (March 2017). "DNA-mediated association of two histone-bound complexes of yeast Chromatin Assembly Factor-1 (CAF-1) drives tetrasome assembly in the wake of DNA replication". eLife. 6: e22799. doi:10.7554/eLife.22799. PMC 5404915. PMID 28315523.
  8. Zhang Z, Shibahara K, Stillman B (November 2000). "PCNA connects DNA replication to epigenetic inheritance in yeast". Nature. 408 (6809): 221–225. Bibcode:2000Natur.408..221Z. doi:10.1038/35041601. PMID 11089978. S2CID 205010657.
  9. Houlard M, Berlivet S, Probst AV, Quivy JP, Héry P, Almouzni G, Gérard M (November 2006). "CAF-1 is essential for heterochromatin organization in pluripotent embryonic cells". PLOS Genetics. 2 (11): e181. doi:10.1371/journal.pgen.0020181. PMC 1630711. PMID 17083276.
  10. Ishiuchi T, Enriquez-Gasca R, Mizutani E, Bošković A, Ziegler-Birling C, Rodriguez-Terrones D, et al. (September 2015). "Early embryonic-like cells are induced by downregulating replication-dependent chromatin assembly". Nature Structural & Molecular Biology. 22 (9): 662–671. doi:10.1038/nsmb.3066. PMID 26237512. S2CID 837230.
  11. Funakoshi Y, Doi Y, Hosoda N, Uchida N, Osawa M, Shimada I, et al. (December 2007). "Mechanism of mRNA deadenylation: evidence for a molecular interplay between translation termination factor eRF3 and mRNA deadenylases". Genes & Development. 21 (23): 3135–3148. doi:10.1101/gad.1597707. PMC 2081979. PMID 18056425.

Further reading
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