Chromatin assembly factor 1

File:Steps in nucleosome assembly.svg

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.{{Cite book|last1=Fang|first1=Dong|url=https://books.google.com/books?id=zGcHEAAAQBAJ&dq=cac1+vs+chaf1a&pg=PA23|title=Histone Mutations and Cancer|last2=Han|first2=Junhong|date=2020-11-06|publisher=Springer Nature|isbn=978-981-15-8104-5|language=en}}{{cite journal|vauthors=Smith S, Stillman B|date=July 1989|title=Purification and characterization of CAF-I, a human cell factor required for chromatin assembly during DNA replication in vitro|journal=Cell|volume=58|issue=1|pages=15–25|doi=10.1016/0092-8674(89)90398-X|pmid=2546672|s2cid=10515064}}{{cite journal|vauthors=Hoek M, Stillman B|date=October 2003|title=Chromatin assembly factor 1 is essential and couples chromatin assembly to DNA replication in vivo|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=100|issue=21|pages=12183–12188|bibcode=2003PNAS..10012183H|doi=10.1073/pnas.1635158100|pmc=218733|pmid=14519857|doi-access=free}}{{Cite journal |last1=Volk |first1=Andrew |last2=Crispino |first2=John D. |date=August 2015 |title=The role of the chromatin assembly complex (CAF-1) and its p60 subunit (CHAF1b) in homeostasis and disease |journal=Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms |volume=1849 |issue=8 |pages=979–986 |doi=10.1016/j.bbagrm.2015.05.009 |issn=0006-3002 |pmc=4515380 |pmid=26066981}}

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.{{cite journal | vauthors = Liu WH, Roemer SC, Zhou Y, Shen ZJ, Dennehey BK, Balsbaugh JL, Liddle JC, Nemkov T, Ahn NG, Hansen KC, Tyler JK, Churchill ME | display-authors = 6 | title = The Cac1 subunit of histone chaperone CAF-1 organizes CAF-1-H3/H4 architecture and tetramerizes histones | journal = eLife | volume = 5 | pages = e18023 | date = September 2016 | pmid = 27690308 | pmc = 5045291 | doi = 10.7554/eLife.18023 | doi-access = free }}{{cite journal | vauthors = Sauer PV, Timm J, Liu D, Sitbon D, Boeri-Erba E, Velours C, Mücke N, Langowski J, Ochsenbein F, Almouzni G, Panne D | display-authors = 6 | title = Insights into the molecular architecture and histone H3-H4 deposition mechanism of yeast Chromatin assembly factor 1 | journal = eLife | volume = 6 | pages = e23474 | date = March 2017 | pmid = 28315525 | pmc = 5404918 | doi = 10.7554/elife.23474 | doi-access = free }}{{cite journal | vauthors = Mattiroli F, Gu Y, Yadav T, Balsbaugh JL, Harris MR, Findlay ES, Liu Y, Radebaugh CA, Stargell LA, Ahn NG, Whitehouse I, Luger K | display-authors = 6 | title = 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 | journal = eLife | volume = 6 | pages = e22799 | date = March 2017 | pmid = 28315523 | pmc = 5404915 | doi = 10.7554/eLife.22799 | doi-access = free }} 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{{cite journal | vauthors = Zhang Z, Shibahara K, Stillman B | title = PCNA connects DNA replication to epigenetic inheritance in yeast | journal = Nature | volume = 408 | issue = 6809 | pages = 221–225 | date = November 2000 | pmid = 11089978 | doi = 10.1038/35041601 | bibcode = 2000Natur.408..221Z | s2cid = 205010657 }}

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.{{cite journal | vauthors = Houlard M, Berlivet S, Probst AV, Quivy JP, Héry P, Almouzni G, Gérard M | title = CAF-1 is essential for heterochromatin organization in pluripotent embryonic cells | journal = PLOS Genetics | volume = 2 | issue = 11 | pages = e181 | date = November 2006 | pmid = 17083276 | pmc = 1630711 | doi = 10.1371/journal.pgen.0020181 | doi-access = free }}

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.{{cite journal | vauthors = Ishiuchi T, Enriquez-Gasca R, Mizutani E, Bošković A, Ziegler-Birling C, Rodriguez-Terrones D, Wakayama T, Vaquerizas JM, Torres-Padilla ME | display-authors = 6 | title = Early embryonic-like cells are induced by downregulating replication-dependent chromatin assembly | journal = Nature Structural & Molecular Biology | volume = 22 | issue = 9 | pages = 662–671 | date = September 2015 | pmid = 26237512 | doi = 10.1038/nsmb.3066 | s2cid = 837230 }}

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.{{cite journal | vauthors = Funakoshi Y, Doi Y, Hosoda N, Uchida N, Osawa M, Shimada I, Tsujimoto M, Suzuki T, Katada T, Hoshino S | display-authors = 6 | title = Mechanism of mRNA deadenylation: evidence for a molecular interplay between translation termination factor eRF3 and mRNA deadenylases | journal = Genes & Development | volume = 21 | issue = 23 | pages = 3135–3148 | date = December 2007 | pmid = 18056425 | pmc = 2081979 | doi = 10.1101/gad.1597707 }}

Chromatin assembly factor 1

Function

Roles

References

Further reading