Meiotic HORMA domain signaling in health and disease

  • Datum: 21.10.2022
  • Uhrzeit: 11:00 - 12:00
  • Vortragender: Dr. Gerben Vader
  • Section of Oncogenetics Department of Human Genetics Cancer Center Amsterdam www.oncogenetics.nl

In mitosis, sequences on sister chromatids are preferred as DNA repair templates, whereas during sexual reproduction interhomolog-based repair is promoted. The switch of template preference during homologous recombinational (HR) repair of DNA breaks is a defining event in eukaryotic sexual reproduction. In budding yeast, a central activity that enforces meiotic interhomolog bias is encoded in a meiosis-specific HORMA domain containing complex, consisting of Red1, Hop1 and Mek1 (i.e., the RHM complex). The functionality of this complex is needed for cell cycle checkpoint control as well as meiosis-specific DNA repair, and assembly/disassembly of RHMc is controlled by the activity of the Pch2/TRIP13 AAA+ ATPAse. Activation of RHM/Mek1 kinase in meiosis – dictated by complex formation and upstream DNA break-dependent signaling – leads to modification of HR factors and the establishment of interhomolog HR repair bias. I will present out work aimed at understanding regulation of checkpoint function as well as interhomolog bias by the HORMA-Pch2/TRIP13 signaling axis. I will demonstrate how expression of RHM components in mitotically-dividing can autonomously establish the RHM complex outside of its physiological environment. This RHM complex can be activated under DNA damaging conditions in mitotically-dividing cells, and we use this system to perform a structure-function analysis of RHM complex formation and Mek1 activation. Expressing active Mek1 in mitosis leads to rad51∆-like DNA break sensitivity, suggesting that activation of the RHM complex is sufficient to reconstitute (parts of) its physiological function in mediating HR-based repair. Human homologs of HOP1 (hsHORMAD1/D2) are often aberrantly re-expressed in cancer cells, and this might lead to specific alterations in DNA repair pathways. I will discuss our ongoing work aimed at understanding how deregulated meiotic HORMA signaling is involved in driving genomic instability associated with human cancer.


To register for the lecture and receive the joining information please email: presse-bio@tuebingen.mpg.de


Zur Redakteursansicht