Laboratory of Genome Integrity

Research at the Laboratory of Integrative Genomics (LIG) centers on elucidating the molecular mechanisms governing DNA damage response and cellular stress pathways. These pathways are activated by a myriad of factors including, but not limited to, erroneous DNA replication, proteotoxicity, mechanical strain, and oxidative damage. Such pathways are pivotal for the sustenance of cancer cells and play a crucial role in conferring therapeutic resistance.

Our investigatory focus encompasses a wide range of cancer-specific hallmarks, such as heightened levels of DNA damage concomitant with mutational burden, challenges in DNA replication fidelity, accumulation of misfolded or dysfunctional proteins, free radical generation, nutrient scarcity, and hypoxic conditions. Through our specialized methods and domain expertise, we aim to directly interrogate and target these stress pathways within the cancer cellular milieu.

The implications of our research are manifold. They extend from the discovery of novel predictive markers to the optimization of existing anticancer regimens and the identification of innovative therapeutic targets. To achieve these aims, the laboratory is segmented into two primary research arms:

The "Cellular Stress" group, headed by Dr. Martin Mistrik, focuses on deciphering the complexities of cellular stress responses and their roles in cancer pathology.

The "DNA Replication Dynamics" group, under the direction of Dr. Pavel Moudry, specializes in exploring the intricacies of DNA replication processes, specifically in the context of malignancies.

Research interests

DNA damage and repair and genomic instability
Proteotoxic stress and proteostasis
Mechanical stress
Oncogenic and free radicals stress
DNA replication and replication stress
PARP enzyme and its targeting

Selected publications

ŠKROTT, Z., M. MISTRÍK, K. ANDERSEN, S. FRIIS, D. MAJERA, J. GURSKÝ, T. OŽDIAN, J. BARTKOVA, Z. TURI, P. MOUDRÝ, M. KRAUS, M. MEDVEDÍKOVÁ, J. VÁCLAVKOVÁ, P. DŽUBÁK, I. VROBEL, P. POUCKOVA, J. SEDLACEK, A. MIKLOVICOVA, A. KUTT, J. MATTOVA, C. DRIESSEN, Q. DOU, J. OLSEN, M. HAJDÚCH, B. CVEK, R. DESHAIES, J. BÁRTEK

Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4. Nature. 2017, 552(7684), 194-199, ISSN: 0028-0836, PMID: 29211715,

CHROMÁ, K., M. MISTRÍK, P. MOUDRÝ, J. GURSKÝ, M. LIPTAY, R. STRAUSS, Z. ŠKROTT, R. VRTEL, J. BARTKOVA, J. KRAMARA, J. BÁRTEK

Tumors overexpressing RNF168 show altered DNA repair and responses to genotoxic treatments, genomic instability and resistance to proteotoxic stress. Oncogene. 2017, 36(17), 2405-2422, ISSN: 0950-9232, PMID: 27841863,

MOUDRÝ, P., K. WATANABE, K. WOLANIN, J. BARTKOVA, I. WASSING, S. WATANABE, R. STRAUSS, R. PEDERSEN, V. OESTERGAARD, M. LISBY, M. ANDUJAR-SANCHEZ, A. MAYA-MENDOZA, F. ESASHI, J. LUKÁŠ, J. BÁRTEK

TOPBP1 regulates RAD51 phosphorylation and chromatin loading and determines PARP inhibitor sensitivity. Journal of Cell Biology. 2016, 212(3), 281-288, ISSN: 0021-9525, PMID: 26811421,

Journals

MAYA-MENDOZA, A., P. MOUDRÝ, J. MERCHUT-MAYA, M. LEE, R. STRAUSS, J. BÁRTEK

High speed of fork progression induces DNA replication stress and genomic instability. Nature. 2018, 559(7713), 279-284, ISSN: 0028-0836, PMID: 29950726,

Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4. Nature. 2017, 552(7684), 194-199, ISSN: 0028-0836, PMID: 29211715,

TURI, Z., M. ŠENKYŘÍKOVÁ, M. MISTRÍK, J. BÁRTEK, P. MOUDRÝ

Perturbation of RNA Polymerase I transcription machinery by ablation of HEATR1 triggers the RPL5/RPL11-MDM2-p53 ribosome biogenesis stress checkpoint pathway in human cells. Cell Cycle. 2017, 17(1), 92-101, ISSN: 1538-4101, PMID: 29143558,

Open positions

Project:	Cellular stress in health and disease
Supervisors:	Mistrík Martin Ph.D., Moudrý Pavel Ph.D., Škrott Zdeněk Ph.D.
Available:	3
Intended for:	Doctoral training