Mutations in the Insulator Protein Suppressor of Hairy Wing Induce Genome Instability
Posted on: 20 March 2019
Preprint posted on 15 February 2019
Article now published in Chromosoma at http://dx.doi.org/10.1007/s00412-020-00743-8
Arrested oogenesis, eggshell patterning defects, and DNA damage accumulation by replication stress, oh my! Drosophila’s Suppressor of Hairy Wing shows that insulator proteins are not just for transcription anymore.
Selected by Maiko Kitaoka
Categories: cell biology, developmental biology
Background
Chromatin insulators are long-range regulatory elements that mediate chromosomal contacts. These contacts allow for proper control of gene expression during development and cellular differentiation, generally preventing enhancer-promoter communication and protecting genes from silencing by heterochromatic mechanisms. These functions are mediated by specific insulator proteins, which bind the insulator DNA sequence to facilitate these DNA-DNA contacts. Insulators and their corresponding proteins have thus been implicated in 3D genome architecture, but their precise roles in mediating genome organization or integrity have not been explored.
Suppressor of Hairy wing (Su(Hw)) binds to the gypsy retrotransposon insulator in Drosophila and, while mutations in insulator proteins are usually lethal, Su(Hw) loss is remarkably not essential for viability. It’s well-known that homozygous females lacking su(Hw) are sterile since oocyte development is arrested midway through oogenesis, but the mutant phenotype has several complex components that have not been analyzed fully. In this preprint, Hsu et al further investigate these defects in oogenesis and define a more detailed role for Su(Hw) that protects the genome from excessive accumulation of DNA damage and instability.
Key findings
The authors first observed that su(Hw) mutants had irregular numbers of nurse cells in egg chambers, which were the result of incomplete or extra cell divisions or egg chamber fusions. Abnormal nurse cell number is also seen in mutants with aberrant piRNA pathway components, as well as proteins that position the microtubule organizing center (MTOC). The MTOC is critical for determination of oocyte polarity and localization of maternal mRNAs, and overall microtubule organization is important for oogenesis. Su(Hw) mutants have weaker, disorganized microtubules, suggesting that loss of Su(Hw) impairs MTOC formation and cannot form the proper microtubule network necessary to allow for egg chamber development through oogenesis. In addition, gurken (Grk) is also mislocalized in these mutants. Normally, Grk is transported along microtubules to the posterior oocyte to allow for dorsoventral axis determination before translocating to the anterior-dorsal corner of the oocyte. However, su(Hw) mutants show failure to translocate Grk, eventually leading to dorsoventral patterning defects in eggshells.
The presence of disorganized microtubules and mislocalized Grk is reminiscent of spindle genes, where cells have excessive DNA double stranded breaks (DSBs) and trigger the ATR/Chk2 DNA damage signaling pathway. The authors show that gH2Av, which marks DNA damage, is increased in su(Hw) mutants as well as su(Hw) and spo11 double mutants. Spo11 induces DSBs normally in meiosis to form crossovers and genetic recombination, so this analysis demonstrates that the DNA damage in su(Hw) mutants is not produced by the meiotic program. In addition, gH2Av persists in later stages of oogenesis in su(Hw) mutants, pointing to an accumulation of non-meiotic DNA damage. Interestingly, this accumulation of DNA damage is not due to overexpression of transposable elements in su(Hw) mutants.
The increased amount of DNA damage likely activates a DNA repair pathway or checkpoint during oogenesis. Given the phenotypic connections to the ATR/Chk2 pathway, the authors examined oogenesis in su(Hw) and ATR double mutants. The loss of ATR partially recovered oocyte development with proper Grk localization and enlargement of the oocyte, suggesting that loss of Su(Hw) triggers the ATR pathway to respond to the accumulated DNA damage. Through careful double mutant analysis of chk1 and chk2 kinases downstream the ATR pathway, the authors were able to show that microtubule disorganization and Grk mislocalization are likely dependent on Chk1-mediated activity. Chk1 has been shown to respond to replication stress, so the loss of Su(Hw) is likely causing replication stress in egg chambers. H4K20 monomethylation, which is also implicated in genome instability from DNA replication mis-regulation, was also increased in su(Hw) mutant ovaries, further supporting the model that the accumulated DNA damage occurs from replication stress.
Lastly, the authors examine a somatic tissue, dividing neuroblasts, to determine whether Su(Hw) has a role in general or ovary-specific genome maintenance. Metaphase spreads from neuroblasts showed several different types of chromosomal aberrations and were less severe in heterozygotes, suggesting that Su(Hw) is important for chromosomal integrity in somatic tissue as well as female germline cells.
This comprehensive work in examining Su(Hw)’s roles in genome integrity appreciates the full complexity of the su(Hw) mutant phenotype. It’s clear that the insulator protein Su(Hw) has functions in oogenesis beyond its classical role in transcriptional regulation, providing a novel mechanistic avenue to examine genome stability through architectural proteins.
Questions for the authors
Is the DNA repair pathway compromised in su(Hw) mutants so that it also becomes inefficient and unable to keep up with the accumulating DNA damage?
The polyploidy and endoreplication of nurse cells means that some regions are underreplicated during oogenesis – are these regions in particular more damaged than other euchromatic and fully replicated regions?
Is it possible that the entire genome is more prone or susceptible to DNA damage without Su(Hw) and how might the loss Su(Hw) mediate this vulnerability?
doi: https://doi.org/10.1242/prelights.8950
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