Epigenetische Mechanismen in der Nukleotid-Excisionsreparatur

• Antragsteller: Dr. Holger Richly
• Fachliche Zuordnung: Allgemeine Genetik und funktionelle Genomforschung ; Biochemie ; Zellbiologie
• Förderung: Förderung von 2014 bis 2018
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 252235824

• Erstellungsjahr: 2018

Zusammenfassung der Projektergebnisse

Our research has refined our current understanding of DNA damage recognition in the GG-NER pathway. Based on our interest in ZRF1, an epigenetic factor that specifically reads the H2A-ubiquitin mark in chromatin, we have revealed a novel multi-protein remodelling mechanism at UV-light damaged chromatin. At the DNA damage site, ZRF1 controls the assembly and disassembly of E3 ubiquitin ligase complexes that drive the ubiquitin signalling cascade as part of the DNA damage response. The article describing these findings had been featured in the Research Highlights in Nature Reviews Molecular Cell Biology, and in the Special Collection: DNA Replication, Recombination and Repair published by the Journal of Cell Biology. We have additionally shown that the H2A-ubiquitin mark has a profound impact on the nuclear organization of the GG-NER pathway. Further, besides remodelling protein complexes ZRF1 also facilitates the chromatin decondensation at the damage site in a parylation dependent manner together with the endoribonuclease DICER and PARP1. Surprisingly, the catalytic function of DICER seems to be dispensible for the chromatin decondensation and DICER seems to rather act as a recruitment platform for DNA repair factors. Apart from ZRF1 and PARP1, DICER interacts with the methyltransferase MMSET. Upon DICER-mediated recruitment to the DNA damage site, MMSET catalyzes the setting of H4K20me2 within chromatin. This specific chromatin mark facilitates the recruitment of the essential nucleotide excision repair factor XPA via the tethering factor 53BP1 and RPA2. Taken together, our research has delineated novel molecular mechanisms in GG-NER, which might over the long run possibly be of interest for clinical research.

Projektbezogene Publikationen (Auswahl)

• ZRF1 mediates Remodeling of E3 ligases at DNA lesion sites during Nucleotide Excision Repair. J Cell Biol. Apr 2016; 213 (2):185-200
  Ekaterina Gracheva, Shalaka Chitale, Thomas Wilhelm, Alexander Rapp, Jonathan Byrne, Jens Stadler, Rebeca Medina, M. Cristina Cardoso and Holger Richly
  
• DICER and ZRF1 contribute to chromatin decondensation during nucleotide excision repair. Nucleic acids research. 2017. Apr 2017; 45 (10): 5901-5912
  Shalaka Chitale and Holger Richly
  
• Nuclear organization of nucleotide excision repair is mediated by RING1B dependent H2A-ubiquitylation. Oncotarget. May 2017; 8 (19): 30870-30887
  Shalaka Chitale and Holger Richly
  
• Regulation of DNA Repair Mechanisms: How the Chromatin Environment Regulates the DNA Damage Response. Int. J. Mol. Sci. Aug 2017; 18 (8): 1715-1725
  Jens Stadler and Holger Richly
  
• Timing of DNA lesion recognition: Ubiquitin Signalling in the NER pathway. Cell Cycle. Jan 2017; 16 (2):163-171
  Shalaka Chitale and Holger Richly
  
• DICER mediated H4K20 dimethylation regulates recruitment of XPA during GG-NER. J Cell Biol. Feb 2018; 217 (2)
  Shalaka Chitale and Holger Richly