Challenging endings: How telomeres prevent fragility

Abstract

It has become apparent that difficulties to replicate telomeres concern not only the very ends of eukaryotic chromosomes. The challenges already start when the replication fork enters the telomeric repeats. The obstacles encountered consist mainly of noncanonical nucleic acid structures that interfere with replication if not resolved.Replication stress at telomeres promotes the formation of so-called fragile telomeres displaying an abnormal appearance in metaphase chromosomes though their exact molecular nature remains to be elucidated. A substantial number of factors is required to counteract fragility. In this review we promote the hypothesis that telomere fragility is not caused directly by an initial insult during replication but it results as a secondary consequence of DNA repair of damaged replication forks by the homologous DNA recombination machinery. Incomplete DNA synthesis at repair sites or partial chromatin condensation may become apparent as telomere fragility. Fragility and DNA repair during telomere replication emerges as a common phenomenon which exacerbates in multiple disease conditions.

The human telomeric proteome during telomere replication

“…After siRNA transfection, telomere morphology of metaphase chromosomes was analyzed by fluorescence in situ hybridization with a telomere specific probe (Figure 5A ). Telomeres that showed smeary or multiple telomeric signals upon gene depletion were recognized as fragile telomeres and inferred to have telomere replication defects ( 15 , 73 ). Apart from the positive control siTRF1, we depleted four additional known telomere replication proteins (BLM, WRN, NONO and SAMHD1) that were present in our QTIP-iPOND samples ( 12 , 14 , 29 , 52 , 74 ).…”

“…Our data support the notion that POT1 is replaced by RPA for telomere replication. Therefore, we suspect that the telomere fragility elicited upon overexpression of POT1 mutants was due to indirect roles of POT1 for telomere maintenance, which may relate to its function in suppressing homology directed repair at telomeres, which in turn promotes telomere fragility ( 33 , 73 ).…”

Mouse HP1γ regulates TRF1 expression and telomere stability

“…Here, we report that HP1γ regulates the expression of many telomere and telomere-accessory factors that are related to facilitating telomere replication and suppressors of telomere fragility [60]. This corresponds to DKC1 that encodes dyskerin involved in the maturation of TERC [61], RTEL1 helicase that facilitates DNA replication through telomeric DNA secondary structures [50] or the BLM helicase that resolves G4 structures [62], many other DNA repair and recombination factors and including TRF1 shelterin factor, that are all transcriptionally downregulated in the absence of HP1γ, especially in males.…”

“…This corresponds to DKC1 that encodes dyskerin involved in the maturation of TERC [61], RTEL1 helicase that facilitates DNA replication through telomeric DNA secondary structures [50] or the BLM helicase that resolves G4 structures [62], many other DNA repair and recombination factors and including TRF1 shelterin factor, that are all transcriptionally downregulated in the absence of HP1γ, especially in males. Mis-regulation of most of these factors have been associated with increased replication stress at telomeres [60], including TRF1 that results in the so-called telomere fragility [35,36,60]. HP1γ's interaction with TIN2 has been shown to be necessary for the establishment of cohesion at human telomeres in S phase [24].…”

Telomere biology disorders: time for moving towards the clinic?

“…Although this complex biochemical structure is essential to prevent erroneous activation of DNA damage responses at chromosomal ends [4], it also makes the replication of DNA ends a challenging process (recently reviewed [5]). In fact, telomeres shorten by up to 200 bp at each cell division, due to the inability of replicative DNA polymerases to fully extend the lagging strand of DNA replication at telomeres [6].…”