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Role of PARP9/DTX3L-dependent H4K91 ubiquitination in the DNA damage response

Grant number: 19/25914-1
Support type:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): February 01, 2020
Effective date (End): February 28, 2023
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal Investigator:Nicolas Carlos Hoch
Grantee:Victoria Chaves Ribeiro
Home Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:18/18007-5 - Protein ADP-ribosylation: DNA damage signalling and impacts on human health, AP.JP

Abstract

DNA damage signalling and repair, which are regulated by a variety of post-translational modifications including ubiquitination and ADP-ribosylation, prevent the genetic alterations that cause Cancer, neurodegeneration and aging. We have previously identified the ADP-ribosyl transferase PARP9 and the ubiquitin ligase DTX3L in an in vitro screen for factors that bind to a DNA damage-induced histone modification. Subsequently, we found that deletion of DTX3L sensitizes cells to an agent that causes DNA damage. Interestingly, mutations in the DTX3L ubiquitination site on Histone H4 cause a rare genetic disorder associated with spontaneous DNA damage and neurodevelopmental defects. Here, we will study in detail how the loss of DTX3L-dependent H4 ubiquitination affects the signalling and repair of DNA damage, to define the cellular roles of this pathway in the DNA damage response. (AU)