DNA Damage to a single chromosome end delays anaphase onset.

Publication Type:

Journal Article

Source:

The Journal of biological chemistry (2014)

Abstract:

Chromosome ends contain nucleoprotein structures known as telomeres. Damage to chromosome ends during interphase elicits a DNA damage response (DDR) resulting in cell cycle arrest. However, little is known regarding the signaling from damaged chromosome ends (defined here as TIPs) during mitosis. In the present study we investigated the consequences of DNA damage induced at a single TIP in mitosis. We used laser microirradiation to damage mitotic TIPs or chromosome arms (Non-TIPs) in PtK2 kidney epithelial cells. We found that damage to a single TIP, but not Non-TIP, delays anaphase onset. This TIP-specific checkpoint response is accompanied by differential recruitment of DDR proteins. While phosphorylation of H2AX and the recruitment of several repair factors, such as Ku70/Ku80, occurs in a comparable manner at both TIP and Non-TIP damage sites, the recruitment of other DDR factors is either not detectable (ATM, MDC1, WRN and FANCD2) or delayed (Nbs1 and BRCA1 as well as ubiquitin signal) at Non-TIPs compared to TIPs. ATR and 53BP1 appear to be absent from both TIPs and Non-TIPs in mitosis. The observed delay in anaphase onset is dependent on the activity of DDR kinases ATM, Chk1, and the spindle assembly checkpoint (SAC) kinase Mps1. Cells damaged at a single TIP or Non-TIP eventually exit mitosis with unrepaired lesions. Damaged TIPs are segregated into micronuclei at a significantly higher frequency than damaged Non-TIPs. Together these findings reveal mitosis-specific DDR uniquely associated with chromosome ends.

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PMCID 
PMC4132783