FBS Colloquia No.158Human Cell Biology Group
| Seminar or Lecture |
Involvement of ubiquitination and SUMOylation in TC-NER Masafumi Saijo [Human Cell Biology Group] Development of splice switching oligonucleotides for treatment of cockayne syndrome Yooksil Sin [National Institutes of Biomedical Innovation, Health and Nutrition] |
|---|---|
| Date and Time | Wednesday, April 26, 2017, 12:15-13:00 |
| Place | 2F Seminar room, BioSystems Building |
| Contact |
Masafumi Saijo |
Involvement of ubiquitination and SUMOylation in TC-NER
Nucleotide excision repair (NER) is a versatile DNA repair pathway that removes a wide range of structurally unrelated bulky, helix-distorting DNA lesions, including UV-induced pyrimidine dimers as well as chemical carcinogen. Transcription-coupled NER (TC-NER) is a subpathway in NER and specifically removes lesions from the transcribed strands of actively transcribed genes. In TC-NER, RNA polymerase II stalled at a lesion on the transcribed strand serves as the damage recognition signal, but the molecular mechanism of TC-NER remains unclear. Several autosomal recessive NER deficiency disorders exist in humans, including xeroderma pigmentosum, Cockayne syndrome (CS), trichothiodystrophy, and UV-sensitive syndrome (UVSS). CS and UVSS patients are specifically deficient in TC-NER. In this colloquium, I show our recent results for the involvement of ubiquitination and SUMOylation in TC-NER.
Development of splice switching oligonucleotides for treatment of cockayne syndrome
Cockayne syndrome (CS) and UV sensitive syndrome (UVSS) are both rare autosomal recessive disorders that have Cockayne syndrome group B (CSB) gene as their responsible gene. CS patients exhibit premature aging, growth failure and several neurologic symptoms but UVSS patients only exhibit right UV sensitivity. The reason why the same responsible gene causes such diseases where severities of clinical symptoms are completely different, is unknown. One possibility is that CSB-PGBD3 protein, one of splicing variants from CSB gene, causes severity in CS group B (CS-B) because it is only expressed in CS. In UVSS, stop codon that is given rise to by mutations at upstream region of PGBD3 coding region inhibits synthesis of CSB-PGBD3 protein. If so, giving rise to stop codon at upstream region of PGBD3 coding region could cures CS-B. Exon skipping by splice switching oligonucleotide (SSO) is able to give rise to such stop codon on CSB mRNA. CSB protein works in nucleotide excision repair, and cells of CS-B patient are hyper sensitive to H2O2 that causes DNA damage. Dysfunction of mitochondrion in CS-B is also reported. Here, we designed and synthesized several SSOs that are able to skip target exon on CSB mRNA, and found that transfection of the highly active SSO to cells of CS-B patients recovered the function of mitochondrion in these cells. I talk about a series of achievements of this treatment strategy in this colloquium.
