Chromatin assembly factor 1 explained

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]}

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. 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.

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.

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.

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]

Further reading

• Cheloufi S, Elling U, Hopfgartner B, Jung YL, Murn J, Ninova M, Hubmann M, Badeaux AI, Euong Ang C, Tenen D, Wesche DJ, Abazova N, Hogue M, Tasdemir N, Brumbaugh J, Rathert P, Jude J, Ferrari F, Blanco A, Fellner M, Wenzel D, Zinner M, Vidal SE, Bell O, Stadtfeld M, Chang HY, Almouzni G, Lowe SW, Rinn J, Wernig M, Aravin A, Shi Y, Park PJ, Penninger JM, Zuber J, Hochedlinger K . 6 . The histone chaperone CAF-1 safeguards somatic cell identity . Nature . 528 . 7581 . 218–224 . December 2015 . 26659182 . 4866648 . 10.1038/nature15749 . 2015Natur.528..218C.
  • December 9, 2015 . Memory loss enables the production of stem cells . ScienceDaily .
• Yu Z, Liu J, Deng WM, Jiao R . Histone chaperone CAF-1: essential roles in multi-cellular organism development . Cellular and Molecular Life Sciences . 72 . 2 . 327–337 . January 2015 . 25292338 . 10.1007/s00018-014-1748-3 . 18355941 . 11114026 .
• Kaufman PD . Want reprogramming? Cut back on the chromatin assembly! . Nature Structural & Molecular Biology . 22 . 9 . 648–650 . September 2015 . 26333710 . 10.1038/nsmb.3081 . 33569420 .
• Polo SE, Almouzni G . Chromatin dynamics after DNA damage: The legacy of the access-repair-restore model . DNA Repair . 36 . 114–121 . December 2015 . 26429064 . 5113751 . 10.1016/j.dnarep.2015.09.014 .
• Wang Z, Wu R, Nie Q, Bouchonville KJ, Diasio RB, Offer SM . Chromatin assembly factor 1 suppresses epigenetic reprogramming toward adaptive drug resistance. . Journal of the National Cancer Center . March 2021 . 1 . 1 . 15–22 . 10.1016/j.jncc.2020.12.003 . 234287367 . free . 39036786 . 11256593 .
• Sauer PV, Gu Y, Liu WH, Mattiroli F, Panne D, Luger K, Churchill ME . Mechanistic insights into histone deposition and nucleosome assembly by the chromatin assembly factor-1 . Nucleic Acids Research . 46 . 19 . 9907–9917 . November 2018 . 30239791 . 6212844 . 10.1093/nar/gky823 .

Notes and References

1. Book: Fang. Dong. Histone Mutations and Cancer. Han. Junhong. 2020-11-06. Springer Nature. 978-981-15-8104-5. en.
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. 10.1016/0092-8674(89)90398-X. 2546672. 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. 2003PNAS..10012183H. 10.1073/pnas.1635158100. 218733. 14519857. free.
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 . 10.1016/j.bbagrm.2015.05.009 . 0006-3002 . 4515380 . 26066981.
5. Liu WH, Roemer SC, Zhou Y, Shen ZJ, Dennehey BK, Balsbaugh JL, Liddle JC, Nemkov T, Ahn NG, Hansen KC, Tyler JK, Churchill ME . 6 . The Cac1 subunit of histone chaperone CAF-1 organizes CAF-1-H3/H4 architecture and tetramerizes histones . eLife . 5 . e18023 . September 2016 . 27690308 . 5045291 . 10.7554/eLife.18023 . free .
6. Sauer PV, Timm J, Liu D, Sitbon D, Boeri-Erba E, Velours C, Mücke N, Langowski J, Ochsenbein F, Almouzni G, Panne D . 6 . Insights into the molecular architecture and histone H3-H4 deposition mechanism of yeast Chromatin assembly factor 1 . eLife . 6 . e23474 . March 2017 . 28315525 . 5404918 . 10.7554/elife.23474 . free .
7. Mattiroli F, Gu Y, Yadav T, Balsbaugh JL, Harris MR, Findlay ES, Liu Y, Radebaugh CA, Stargell LA, Ahn NG, Whitehouse I, Luger K . 6 . 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 . March 2017 . 28315523 . 5404915 . 10.7554/eLife.22799 . free .
8. Zhang Z, Shibahara K, Stillman B . PCNA connects DNA replication to epigenetic inheritance in yeast . Nature . 408 . 6809 . 221–225 . November 2000 . 11089978 . 10.1038/35041601 . 2000Natur.408..221Z . 205010657 .
9. Houlard M, Berlivet S, Probst AV, Quivy JP, Héry P, Almouzni G, Gérard M . CAF-1 is essential for heterochromatin organization in pluripotent embryonic cells . PLOS Genetics . 2 . 11 . e181 . November 2006 . 17083276 . 1630711 . 10.1371/journal.pgen.0020181 . free .
10. Ishiuchi T, Enriquez-Gasca R, Mizutani E, Bošković A, Ziegler-Birling C, Rodriguez-Terrones D, Wakayama T, Vaquerizas JM, Torres-Padilla ME . 6 . Early embryonic-like cells are induced by downregulating replication-dependent chromatin assembly . Nature Structural & Molecular Biology . 22 . 9 . 662–671 . September 2015 . 26237512 . 10.1038/nsmb.3066 . 837230 .
11. Funakoshi Y, Doi Y, Hosoda N, Uchida N, Osawa M, Shimada I, Tsujimoto M, Suzuki T, Katada T, Hoshino S . 6 . Mechanism of mRNA deadenylation: evidence for a molecular interplay between translation termination factor eRF3 and mRNA deadenylases . Genes & Development . 21 . 23 . 3135–3148 . December 2007 . 18056425 . 2081979 . 10.1101/gad.1597707 .