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Maciej Kliszczak

Msc, MEng, PhD


Post-doctoral Researcher

Characterisation of serine protease FAM111B mutated in Hereditary Fibrosing Poikiloderma syndrome.

Background

Maciej, originally from Poland, studied Biotechnology with a specialization in Medicinal Chemistry at the Wroclaw University of Science and Technology (PWr). His MSc/MEng project, supervised by Prof. Jozef Oleksyszyn and Dr. Marcin Sienczyk, focused on designing, synthesizing, and testing small molecule inhibitors of serine proteases as potential cancer growth inhibitors. During this time, Maciej also gained his first cell biology experience at Dr. Michael P. Carty's lab at the National University of Ireland, Galway (NUIG), where he studied the effects of protease inhibitors on cancer cell survival and explored how Polymerase Eta deficiency impacts DNA repair in human cells.

After successfully defending his Master's project, Maciej pursued a Doctor of Philosophy (DPhil) degree at NUIG under Prof. Ciaran Morrison, investigating the roles of the Smc5/6 complex in DNA repair. Following this, he moved to the University of Copenhagen to work with Prof. Ian D. Hickson on the roles of the RECQL4 helicase in human aging.

A few years later, Maciej relocated to Oxford, where he began postdoctoral research in the laboratories of Prof. Andrew Wilkie and Prof. Wojciech Niedzwiedz, studying the impact of CDC45 mutations on craniosynostosis pathology. He then joined the Structural Genomics Consortium (SGC) in Oxford, working with Dr. Nicola Burgess-Brown on small molecule screening and protein production methods.

When SGC transitioned into the Centre for Medicines Discovery (CMD), Maciej moved to the Centre for Human Genetics to collaborate with Dr. Catherine M. Green (OBE for her work on the COVID-19 vaccine), investigating the cellular mechanisms of FAM111B serine protease mutations, which cause Hereditary Fibrosing Poikiloderma (HFP).

In 2022, Maciej rejoined CMD as part of the Oxford Drug Discovery Institute (ODDI), where he now leads small molecule and genetic screening projects aimed at discovering novel targets and treatments for neurodegenerative diseases

Qualifications

https://www.linkedin.com/in/maciej-kliszczak-msc-meng-phd-b247912b/

Research

Two Pore Channel 2 (TPC2) is part of an ancient family of voltage-gated channels. It is primarily localized to the endolysosomal compartment, where it plays a crucial role in maintaining the specific conditions required within these vesicles. TPC2 is essential for robust endocytosis, and its activity has been linked to the prevention of viral infections, including Ebola and COVID-19, as well as neurodegeneration.

We are currently investigating the lysosomal TPC2 calcium channel as a potential drug target for neurodegeneration. We have developed cellular assays to screen for small molecule inhibitors of TPC2 activity. By integrating a range of robotic solutions with the FLIPR (Fluorescent Imaging Plate Reader), we assess the activity of membrane-targeted TPC2 following treatment with small molecule libraries. Our goal is to identify a specific, brain-penetrant inhibitor of the lysosomal TPC2 channel.

In parallel, we have established a genetic screening assay utilizing CRISPR-Cas9 technology and TPC2-GECI as a reporter, to modulate TPC2 activity by targeting its modulators. Currently, we are exploring several novel targets that may play a role in regulating the activity of the lysosomal TPC2 channel.

publication

Kliszczak M., Moralli D., Jankowska J.D., Bryjka P., Subha Meem L., Goncalves T., Hester S.S., Fischer R., Clynes D., Green C.M. (2023). Loss of FAM111B protease mutated in hereditary fibrosing poikiloderma negatively regulates telomere length. Front Cell Dev Biol. 11:1175069.

Bulbrook D., Brazier H., Mahajan P., Kliszczak M., Fedorov O., Marchese F.P., Aubareda A., Chalk R., Picaud S., Strain-Damerell C., Filippakopoulos P., Gileadi O., Clark AR., Yue W.W., Burgess-Brown N.A., Dean J.L.E. (2017). Tryptophan-Mediated Interactions between Tristetraprolin and the CNOT9 Subunit Are Required for CCR4-NOT Deadenylase Complex Recruitment. J Mol Biol. 430(5):722-736.

¥Fenwick, A.L., ¥Kliszczak M., et al. (2016). Mutations in CDC45, encoding en essential component of the pre-initiation complex, cause Meier-Gorlin syndrome and craniosynostosis. American Journal for Human Genetics 99, 125-138.

Kliszczak, M., Sedlackova, H., Pitchai, G.P., Streicher, W.W., Krejci, L. and Hickson, I.D. (2015). Interaction of RECQ4 and MCM10 is important for efficient DNA replication origin firing in human cells. Oncotarget 6, 40464-40479.

¥Kliszczak, M., ¥Stephan A.K. Flanagan A.M. and Morrison C.G. (2012). SUMO ligase activity of vertebrate Mms21/Nse2 is required for efficient DNA repair but not for Smc5/6 complex stability. DNA repair 11, 799-810.

¥Stephan, A.K., ¥Kliszczak, M., Dodson, H., Cooley, C., and Morrison, C.G. (2011). Roles of vertebrate Smc5 in sister chromatid cohesion and homologous recombinational repair. Molecular and Cellular Biology 31, 1369-1381.

¥Stephan, A.K., ¥Kliszczak, M., and Morrison, C.G. (2011). The Nse2/Mms21 SUMO ligase of the Smc5/6 complex in the maintenance of genome stability. FEBS Letters 585, 2907-2913.

Sienczyk, M., Kliszczak, M., and Oleksyszyn, J . (2006). Synthesis of isocyanide derivatives of alpha-aminoalkylphosphonate diphenyl esters. Tetrahedron Letters 47, 4209-4211.

¥ - joint first authorship