RecQ4 – a protein hub required for proper replication and recombination and its implications in Rothmund-Thomson Syndrome

Kód projektu
MUNI/G/1594/2019
Období řešení
3/2020 - 12/2022
Investor / Programový rámec / typ projektu
Masarykova univerzita
Fakulta / Pracoviště MU
Přírodovědecká fakulta
Další fakulta/pracoviště MU
Lékařská fakulta
Další fakulta/pracoviště MU
Středoevropský technologický institut

Mutations in RECQ4 helicase cause the Rothmund-Thomson syndrome. The disease is characterized by chromosome fragility, premature aging, developmental abnormalities and predisposition to cancer. RecQ4 participates in several cellular processes, including DNA replication, DNA damage response, telomere and mitochondrial maintenance. However, it is not clear which impaired functions of RECQ4 trigger the pathogenic effects. We have identified several novel RecQ4 interacting partners mediated by the conserved N-terminal domain required for cell viability. Here we propose a multidisciplinary set of biochemical, biophysical, structural, cellular and genetic approaches to understand the molecular function of RecQ4 protein in cells and its correlation to disease development. We set three goals to unravel the roles of RecQ4 during replication and resolution of replication/recombination intermediates. Krejci’s lab will focus on biochemical characterization of the above-mentioned protein interactions and their effect on replication initiation and progression, as well as resolution of stalled intermediates in human cell lines. Tripsianes’ group will focus on structural and biophysical characterisation of interaction interfaces and identify separation of function mutants. Silva’s team will nicely complement the biological role of RecQ4 in the C.elegans model system. The proposed synergy promises to dissect RecQ4 multiple functions in genome maintenance, which in turn will offer a better understanding on the development of RECQ4 associated diseases.

Publikace

Počet publikací: 2


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