RT info:eu-repo/semantics/doctoralThesis
T1 ldentification and characterization of novel enzymes involved in the DNA damage response in human cells
A1 Hernández Reyes, Yeray
AB A correct DNA damage response is critical in maintaining genome integrityand the prevention of cancer. Efficient DNA repair requires the correct andtimely coordination of a multitude of signaling events, in whichpost-translational modifications play a critical role. Here we investigateenzymes important in the cellular response to DNA damage and the molecularmechanisms of how these enzymes help preventing genome instability. Weidentified ubiquitin hydrolase USP29 as novel regulator of SETD8, a methyltransferase important for the recruitment of 53BP1 to sites of DNA damage bycontrolling histone H4K20 methylation. USP29 interacts with anddeubiquitinates SETD8 in vivo. USP29 regulates DNA damage-inducedH4K20 methylation and focus formation of 53BP1 and depletion of USP29increases the cellular sensitivity to irradiation. These results suggest thatUSP29 is critical for the DNA damage response and cell survival. Uponexamining of interactors of lysine demethylase PHF2, described to controlhomolog-directed repair of double strand breaks, we identified USP36 andTRIP13. These novel interactors might collaborate with PHF2 in themaintenance of genome stability. Finally, we describe a role for RNA helicasesDDX18, DDX37 and DDX50 in the prevention of DNA damage, likely by theregulation of transcription-dependent R-loop formation. Together, thesefindings help our understanding of the maintenance of genome integrity andcould be of use for the identification of novel therapeutic targets for cancertreatment.
YR 2024
FD 2024
LK http://riull.ull.es/xmlui/handle/915/38048
UL http://riull.ull.es/xmlui/handle/915/38048
LA en
NO Grants SAF2016-80626-R funded by MCIN/AEI/10.13039/ 501100011033 and by “ERDF A way of making Europe” and PID2019-109222RB-I00 funded by MCIN/AEI/10.13039/501100011033, both to V. A. J. Smits and R. Freire.
DS Repositorio institucional de la Universidad de La Laguna
RD 23-dic-2024