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Review
. 2023 Nov;597(22):2782-2790.
doi: 10.1002/1873-3468.14685. Epub 2023 Jun 25.

The secret life of chromatin tethers

Anna A Kiseleva  1 , Andrey Poleshko  1
Affiliations
Review

The secret life of chromatin tethers

Anna A Kiseleva et al. FEBS Lett. 2023 Nov.

Abstract

The nuclear envelope plays an essential role in organizing the genome inside of the nucleus. The inner nuclear membrane is coated with a meshwork of filamentous lamin proteins that provide a surface to organize a variety of cellular processes. A subset of nuclear lamina- and membrane-associated proteins functions as anchors to hold transcriptionally silent heterochromatin at the nuclear periphery. While most chromatin tethers are integral membrane proteins, a limited number are lamina-bound. One example is the mammalian proline-rich 14 (PRR14) protein. PRR14 is a recently characterized protein with unique function that is different from other known chromatin tethers. Here, we review our current understanding of PRR14 structure and function in organizing heterochromatin at the nuclear periphery.

Keywords: HP1; LADs; PRR14; nuclear lamina; peripheral heterochromatin.

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Figures

Figure 1.
Figure 1.. A schematic illustration of structural and functional elements of human PRR14 protein.
Among known functional motifs are two nuclear-localization sequences (NLS): NLS1 (30–36aa) and NLS2 (518–534aa); two HP1-binding motifs, LAVVL (52–56aa) and LVVML (153–157aa); two lamina-binding domains (LBD): LBD1 (231–282aa) and LBD2 (283–351aa); and a PP2A-binding site (495–500aa) that promotes interaction with PP2A B56α subunit.
Figure 2.
Figure 2.. A schematic model of PRR14 as a tether of HP1-bound heterochromatin to the nuclear lamina.
PRR14 is associated with the nuclear lamina, which distinguishes it from other mammalian inner-nuclear membrane (INM) tethers (e.g., LBR, LEM-domain proteins). PRR14 proteins are uniformly distributed at the nuclear periphery creating a “sticky” surface for HP1-bound heterochromatin. Association of PRR14 with the nuclear lamina is regulated via phosphorylation of PRR14 lamina-binding domain.
Figure 3.
Figure 3.. A schematic model of PRR14 function during mitosis.
In prophase, multiple phosphorylation events occur, including phosphorylation of Ser10 on histone H3 tail (H3S10p) that displaces HP1 proteins from H3K9-methylated chromatin. At the same time, PRR14 is observed to detach from the nuclear lamina, potentially via phosphorylation of the PRR14 LBD. In anaphase, chromatin dephosphorylation triggers reassembly of the HP1/PRR14 complex of the mitotic chromosomes. During telophase progression and nuclear envelope reassembly, PRR14 is proposed as a platform for nuclear lamina formation on the surface of mitotic chromatin and re-establishment of heterochromatin-nuclear lamina contacts.
Figure 4.
Figure 4.. A comparison of PRR14 tethering function in interphase and mitotic cells.
In interphase cells, PRR14 coats the nuclear lamina and provides a binding surface for heterochromatin at the nuclear periphery. In telophase, PRR14 coats mitotic chromatin and is predicted to promote nuclear lamina reassembly on the surface of mitotic chromatin.
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