Centrosome cohesion: functions of C-NAP1
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Double stranded DNA encodes the genetic material of the cell. Replication and segregation cycles are regulated in order to maintain the integrity of the DNA sequence from one cell cycle to the next. Detection of lesions in the genetic material directs specific signalling and repair pathways to conserve the DNA sequence at the site of damage. The DNA damage response can arrest the cell cycle. Functions of other organelles, such as the centrosome, can proceed during this time, although their activities can become desynchronized from the cell cycle. The main microtubule organising centre in animal cells is the centrosome. The centrosome is composed of two barrels of microtubule triplets connected by a fibrous intercentriolar linker held in a lattice of proteins called the pericentriolar material and surrounded by a clustering of centriolar satellite complexes. C-NAP1 anchors the linker to the centrioles and is removed following centrosome duplication to facilitate the centrosome-mediated organisation of the bipolar spindle in mitosis. C-NAP1 depletion causes premature loss of centrosome cohesion and centrosome splitting. To address the impact of DNA damage on split centrosomes, we investigated C-NAP1 in chicken and human systems. We observed that chicken C-NAP1 localises to the centrosome, between the centrioles. Conditional depletion of chicken C-NAP1 using an auxin-inducible degron did not affect centrosome cohesion or centrosomal responses to DNA damage. We generated stable human cell lines with a disrupted C-NAP1 coding region and noticed a significant increase in split centrosomes. We also discovered a disorganised localisation pattern of centriolar satellite complexes in cells lacking C-NAP1, where the key satellite components PCM1 and OFD1 showed decreased clustering at the centrosome although their total expression remained unchanged. The ability to generate primary cilia was not affected by C-NAP1 loss, although we observed the formation of aberrant rootletin structures in the cytosol of ciliated cells. We exposed C-NAP1-disrupted cells to ionising radiation to induce a DNA damage response and found the level of centriole amplification was decreased when compared to wildtype cells. We propose that the decrease in the local concentration of centriolar satellite components at the centrosome hinders the DNA damage-induced amplification of centrioles.
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