DNA damage signalling targets the kinetochore to promote chromatin mobility

Abstract

In budding yeast, chromatin mobility increases after a DNA double-strand break (DSB). This increase is dependent on Mec1, the yeast ATR kinase, but the targets responsible for this phenomenon are unknown. Here we report that the Mec1-dependent phosphorylation of Cep3, a kinetochore component, is required to stimulate chromatin mobility after DNA breaks. Cep3 phosphorylation counteracts a constraint on chromosome movement imposed by the attachment of centromeres to the spindle pole body. A second constraint, imposed by the tethering of telomeres to the nuclear periphery, is also relieved after chromosome breakage. A non-phosphorylatable Cep3 mutant that impairs DSB-induced chromatin mobility is proficient in DSB repair, suggesting that break-induced chromatin mobility may be dispensable for homology search. Rather, we propose that the relief of centromeric constraint promotes cell cycle arrest and faithful chromosome segregation through the engagement of the spindle assembly checkpoint.

Keep moving and stay in a good shape to find your homologous recombination partner

“…However, this correlation could stem from Ino80-mediated effects other than mobility increase. The fact that some mutants affected in DSB-induced mobility show no defect in HR efficiency further questions this functional relationship (Lee et al 2016;Strecker et al 2016).…”

“…Both global and local increase in motion depend on checkpoint activation and diverse, non-exclusive, mechanisms have been proposed (for a Review Smith and Rothstein 2017;Zimmer and Fabre 2018). First, a checkpoint-mediated disruption of centromeres anchoring has recently been proposed to participate in this DSB-induced chromatin mobility (Strecker et al 2016). Second, a change in chromatin stiffness caused by both local and global chromatin remodelling may account for increased motion (Hauer et al 2017).…”

“…In S. cerevisiae, the chromosomic DNA motion is limited by the tethering of centromeres and telomeres to nuclear membrane components (Hediger et al 2002;Winey and Bloom 2012;Verdaasdonk et al 2013;Strecker et al 2016). This constraint is at least partially relieved in response to DNA damage.…”

A Life Investigating Pathways That Repair Broken Chromosomes

“…There is a much smaller effect on unbroken chromosomes. However, two recent studies have suggested that this increase in mobility does not improve the ability of a distant donor locus to repair a DSB, for example, in competition with an intrachromosomal donor (70,126). In fact, much of the increase in mobility can be attributed to DNA damage checkpoint kinase phosphorylation of a key kinetochore protein, Cep3, and the untethering of telomeres from the…”

“…nuclear periphery (126). However, there is much to be explored here; the centromere/telomere modifications do not explain why mutations in a number of recombination proteins (Rad51, Rad54, Sae2, or chromatin factors such as Htz1 or Ino80) should reduce this increase in mobility.…”