Perinuclear tethers license telomeric DSBs for a broad kinesin- and NPC-dependent DNA repair process

Abstract

DNA double-strand breaks (DSBs) are often targeted to nuclear pore complexes (NPCs) for repair. How targeting is achieved and the DNA repair pathways involved in this process remain unclear. Here, we show that the kinesin-14 motor protein complex (Cik1-Kar3) cooperates with chromatin remodellers to mediate interactions between subtelomeric DSBs and the Nup84 nuclear pore complex to ensure cell survival via break-induced replication (BIR), an error-prone DNA repair process. Insertion of a DNA zip code near the subtelomeric DSB site artificially targets it to NPCs hyperactivating this repair mechanism. Kinesin-14 and Nup84 mediate BIR-dependent repair at non-telomeric DSBs whereas perinuclear telomere tethers are only required for telomeric BIR. Furthermore, kinesin-14 plays a critical role in telomerase-independent telomere maintenance. Thus, we uncover roles for kinesin and NPCs in DNA repair by BIR and reveal that perinuclear telomere anchors license subtelomeric DSBs for this error-prone DNA repair mechanism.

Nuclear compartmentalization of DNA repair

“…It was shown that the remodeler SWR-C and deposition of H2AZ is necessary for the break relocation to both sites during the early steps [78 ]. Another report reveals the role of the kinesin-14 motor protein complex in the transient relocation of telomeric and non-telomeric DSBs to the nuclear pores [79]. Moreover, relocation to the pores happens throughout the cell cycle, whereas relocation to nuclear envelope happens only in S-G2 in a manner that requires INO80-C and RAD51 [78].…”

Relocalization of DNA lesions to the nuclear pore complex

“…2009; Chung et al. 2015). The lesions that have been found to relocate to the yeast nuclear pore or NE and the circumstances required are summarized in Tables 1 and 2, respectively.…”

“…Recently, it was found that a subtelomeric DSB moves from the NE location normally occupied by telomeres to the NPC, and this movement was dependent on cohibin, a telomere tethering complex, kinesin14, a motor protein complex and α-tubulin (Chung et al. 2015). The authors propose that an active microtubule-motor process moves the damaged telomere between sites.…”

“…For a subtelomeric DSB, survivors usually used BIR to repair, which was reduced in mutants with defective NPC localization, and artificial tethering to the pore hyperactivated BIR (Chung et al. 2015). Pore-dependent BIR events assayed with a variety of reporters were all highly dependent on Rad52 and Pol32, two proteins previously established to be necessary for ectopic BIR (Anand, Lovett and Haber 2013; Chung et al.…”

“…Pore-dependent BIR events assayed with a variety of reporters were all highly dependent on Rad52 and Pol32, two proteins previously established to be necessary for ectopic BIR (Anand, Lovett and Haber 2013; Chung et al. 2015). Eroded telomeres can be rescued by either type I or type II recombination, with type II being more prominent in survivors; however, NPC mutants exhibit severely reduced numbers of type II recombinants (Churikov et al.…”