Loss of telomere silencing is accompanied by dysfunction of Polo kinase and centrosomes during Drosophila oogenesis and early development

Abstract

Telomeres are nucleoprotein complexes that protect the ends of eukaryotic linear chromosomes from degradation and fusions. Telomere dysfunction leads to cell growth arrest, oncogenesis, and premature aging. Telomeric RNAs have been found in all studied species; however, their functions and biogenesis are not clearly understood. We studied the mechanisms of development disorders observed upon overexpression of telomeric repeats in Drosophila. In somatic cells, overexpression of telomeric retrotransposon HeT-A is cytotoxic and leads to the accumulation of HeT-A Gag near centrosomes. We found that RNA and RNA-binding protein Gag encoded by the telomeric retrotransposon HeT-A interact with Polo and Cdk1 mitotic kinases, which are conserved regulators of centrosome biogenesis and cell cycle. The depletion of proteins Spindle E, Ccr4 or Ars2 resulting in HeT-A overexpression in the germline was accompanied by mislocalization of Polo as well as its abnormal stabilization during oogenesis and severe deregulation of centrosome biogenesis leading to maternal-effect embryonic lethality. These data suggest a mechanistic link between telomeric HeT-A ribonucleoproteins and cell cycle regulators that ensures the cell response to telomere dysfunction.

Mod(mdg4) variants repress telomeric retrotransposon HeT-A by blocking subtelomeric enhancers

“…1I), suggesting defective ovulation. De-repression of HeT-A in germ cells causes abnormal mitosis in early embryos and leads to lethality with maternal effect (Morgunova et al ., 2015; Morgunova et al ., 2021). However, these mutants lay eggs.…”

“…These unique features of telomere maintenance by retrotransposons in D. melanogaster look like a symbiosis between host and retrotransposon (Pardue and Debaryshe, 2002). However, de-repression of HeT-A retrotransposon in germ cells causes severe embryo abnormalities (Morgunova et al, 2015; Morgunova et al, 2021), and recent genomic analysis of the other Drosophila species has suggested that these retrotransposons have evolved very rapidly and replicated their copy number selfishly rather than symbiotically (Saint-Leandre et al, 2020; Saint-Leandre et al, 2019). Therefore, the host must regulate the activity of telomeric retrotransposons.…”

Kinesin Family Member C1 (KIFC1/HSET): A Potential Actionable Biomarker of Early Stage Breast Tumorigenesis and Progression of High-Risk Lesions

“…TEIF was found to positively correlate with CA in colorectal tumors [75]. Telomere dysfunction induced in Drosophila oogenesis caused deregulation of centrosome biogenesis, leading to embryonic lethality [22]. Since CA also elicits CIN and genomic instability, telomere dysfunction may cause CIN and aneuploidy to arise in pre-neoplastic HMECs or early stage lesions.…”

“…Specifically, CA has been found to increase from atypical ductal hyperplasia (ADH) to ductal carcinoma in situ (DCIS), to increase with higher DCIS grade, and to be more prevalent in TNBC versus non-TNBC tumors [20,21]. CA has also been shown to be associated with chromosomal instability (CIN) and aneuploidy in early stage breast lesions as well as being linked to cell cycle deregulation, telomere dysfunction, and cellular senescence [15,16,[22][23][24][25]. Furthermore, induction of CA in non-transformed cell lines has been shown to be sufficient to induce tumorigenesis and to mimic oncogene-induced cellular invasion [26][27][28][29].…”

Mod(mdg4) variants repress telomeric retrotransposon HeT-A by blocking subtelomeric enhancers

“…These unique features of telomere maintenance by retrotransposons in D. melanogaster resemble a symbiosis between the host and retrotransposon ( 20 ). However, de-repression of HeT-A retrotransposon in germ cells causes severe embryo abnormalities ( 33 , 34 ), and a recent genomic analysis of other Drosophila species has suggested that these retrotransposons evolve rapidly and replicate their copy number selfishly rather than symbiotically ( 21 , 26 , 35 ). Therefore, the host must regulate the telomeric retrotransposon activity.…”