The fission yeast DNA structure checkpoint protein Rad26ATRIP/LCD1/UVSD accumulates in the cytoplasm following microtubule destabilization

Abstract

Background: DNA structure checkpoints are conserved eukaryotic signal transduction pathways that help preserve genomic integrity. Upon detecting checkpoint signals such as stalled replication forks or double-stranded DNA breaks, these pathways coordinate appropriate stress responses. Members of the PI-3 kinase related kinase (PIKK) family are essential elements of DNA structure checkpoints. In fission yeast, the Rad3 PIKK and its regulatory subunit Rad26 coordinate the detection of checkpoint signals with pathway outputs.

A Genomic Multiprocess Survey of Machineries that Control and Link Cell Shape, Microtubule Organization, and Cell-Cycle Progression

“…We conclude that the DDR specifically induces stabilisation of interphase microtubules, revealing a conserved link between the DDR and cytoskeletal control in cells. Though some links between those two machineries have been reported (Baschal et al, 2006; Lee et al, 2010; Lee et al, 2011; Xie et al, 2011), the conserved link described here points to a more general connection, whose exact physiological role and mechanistic details - in particular the cytoskeletal DDR target(s) involved - will need to be clarified. This might be of particular therapeutic relevance as a combination of cytostatic doses of DNA-damaging drugs with microtubule drugs has been shown to result in selective cytotoxicity and radio-/chemo-sensitisation in some cancer cells (Baumgart et al, 2012; Blagosklonny et al, 2000; Lee et al, 2011).…”

Effect of Surface Coating of Gold Nanoparticles on Cytotoxicity and Cell Cycle Progression

“…Increased levels of PCNA can cause cell cycle arrest in G 0 /G 1 through the inactivation of CDK4/6. Moreover, increased levels of p53 and PCNA can contribute to microtubule damage [25,29].…”

Characterization of hNek6 Interactome Reveals an Important Role for Its Short N-Terminal Domain and Colocalization with Proteins at the Centrosome

“…Although there is no study to date characterizing the mammalian protein, Rad26 is described in yeast to be required for two processes dependent on microtubules: chromosome segregation and cell polarity. 64 Therefore, associated to the fact that RAD26-like colocalizes with hNek6 in human cells (Figure 6H) and is also a substrate in vitro (Figure 5B), it is an interesting interacting target to be studied, as it might link hNek6 to the DNA repair function and/ or cell cycle in processes dependent on microtubules. Another protein identified related to DNA repair is PHF1, a polycomb group (PcG) chromatin modifier which was recently involved in the response to DNA double-strand breaks (DSBs), 65 and was found to colocalize with hNek6 in human cells (Figure 6G).…”

“…In a previous yeast two-hybrid screen performed by our group using hNek1 as bait, proteins that take part in the dsDNA repair during the G2/M transition phase of the cell cycle were identified, and three recent studies suggest that Nek1, Nek6 and Nek11 are important regulators of this biological process. − Besides the double-strand-break repair protein Rad21 homologue (hHR21; RAD21), which is involved in double-strand-break repair during the cell cycle, we also identified RAD26-like in our screenings. Although there is no study to date characterizing the mammalian protein, Rad26 is described in yeast to be required for two processes dependent on microtubules: chromosome segregation and cell polarity . Therefore, associated to the fact that RAD26-like colocalizes with hNek6 in human cells (Figure H) and is also a substrate in vitro (Figure B), it is an interesting interacting target to be studied, as it might link hNek6 to the DNA repair function and/or cell cycle in processes dependent on microtubules.…”