Condensin II subunit NCAPH2 associates with shelterin protein TRF1 and is required for telomere stability

Abstract

Condensin II subunits are known to be expressed and localized to interphase nuclei of eukaryotic cells. Although some studies have shown that condensin II likely exerts axial compaction forces, organizes chromosome territories, and has possible transcriptional modulatory functions, the full range of condensin II interphase activities are not known. In particular, it is not known if condensin II interphase activities are generally genome‐wide or if they have additional local activities unique to specific chromosomal structures such as telomeres. Here, we find that NCAPH2 interacts with TRF1 and these two proteins co‐localize at telomeres. Depletion of NCAPH2 leads to ATR‐dependent accumulation of 53BP1 and γH2AX DNA damage foci, including damage specific to telomeres. Furthermore, depletion of NCAPH2 results in a fragile telomere phenotype and apparent sister‐telomere fusions only days after NCAPH2 depletion. Taken together these observations suggest that NCAPH2 promotes telomere stability, possibly through a direct interaction with the TRF1 shelterin component, and prevents telomere dysfunction resulting from impaired DNA replication. Because proper telomere function is essential for chromosome integrity these observations reveal a previously unappreciated function for NCAPH2 in ensuring genome and telomere stability.

Cancer‐associated mutations in the condensin II subunit CAPH2 cause genomic instability through telomere dysfunction and anaphase chromosome bridges

“…Our data indicate that cells with ≥4 γH2AX foci are not enriched in S‐phase (Figure 5a,b), and that knockdown of CAPH2 or expression of R551P mutant CAPH2 causes G1 arrest/delay (Figure 5c–g). RNAi depletion of CAPH2 causes RPA recruitment to telomeres (Wallace et al, 2019), indicating a role for condensin II in preventing ssDNA formation at telomeres. It is possible that ssDNA present at telomeres leads to sister chromatid telomere fusions observed after depletion of CAPH2 (Wallace et al, 2019), and that these fusions cause chromosome breakages during mitosis that are inherited as damaged DNA in G1 of the next cell cycle (Giunta et al, 2010; Lezaja & Altmeyer, 2018).…”

Condensin complexes: understanding loop extrusion one conformational change at a time

“…In fact, the actions of condensin I and II in vivo could also be further modulated and regulated by co-factors present in the cellular environment. There is an ever-increasing list of condensin I or II specific co-factors including but not limited to, the chromo kinesin KIF4A, telomere-associated TRF1 and TANK1, cell cycle factors RB1, pRB and Plk1, chromatin modeller component, Arid1a, the transcription factor, TFIIIC and DNA damage response factor, MCPH1 [78][79][80][81][82][83][84][85][86][87]. The role of condensin I and II binding partners in the structural organisation of the genome is largely unknown.…”

Chromatin Remodelers in the 3D Nuclear Compartment

“…ARID1A plays an important role at the enhancer regions. ChIP-seq experiments using ovarian cancer cell-lines demonstrated that more than 80% of the peaks are localized at the enhancers and promoters, and that ARID1A co-localizes with a subunit of the condensin complex II called NCAPH2, which has recently been shown to associate with the shelterin protein, TRF1, and regulate telomeric stability ( Wallace et al, 2019 ). ARID1A knockout affected the binding of NCAPH2 at H3K27Ac-marked enhancers genome-wide.…”