Max Planck Research Group Jachimowicz

Mechanisms of DNA Repair

Our cells have sophisticated repair mechanisms to repair DNA damage. With age, these DNA repair mechanisms become impaired, leading to the accumulation of DNA damage and disruption of cellular function. The goal of our research is to gain a better understanding of the relationship between DNA repair and ageing.

The integrity of our genome needs to be preserved to ensure the faithful passage of genetic information to our progeny. An extensive network of DNA repair pathways ensure that the consequences of DNA damage are held to a minimum. Defects in DNA repair pathways thus promote genome instability and are a central contributor to ageing and carcinogenesis.

Supporting the importance of genome stability on an organismal level, human genome instability syndromes frequently share clinical features of premature ageing and ageing-associated diseases, including increased cancer susceptibility, neurodegeneration, and immunodeficiency. For example, the identification of Ataxia-telangiectasia - the disease underlying germline ATM mutations- contributed significantly to our mechanistic understanding of the DNA damage response, as well cancer- and ageing-related pathways. Somatic mutations in ATM are further commonly found in mantle cell lymphoma, a mature B-cell lymphoma typically affecting the elderly, for which mechanism-based therapies are scarce with poor overall treatment outcome.

Our research aims to provide a better understanding of the relationship between genome maintenance, ageing, and cancer, in an interdisciplinary approach. We dissect defects in DNA repair pathways in patients with genome instability syndromes and in patients suffering from mantle cell lymphoma, providing a rich and unparalleled opportunity to uncover novel pathways in a meaningful organism. We utilize tools involving biochemistry, cell biology, and computational biology, and transfer these findings to modern mouse genetics, that will ultimately lead to genetically-informed therapies for patients suffering from cancer and ageing associated diseases.

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Selected publications 

UBQLN4 Represses Homologous Recombination and Is Overexpressed in Aggressive Tumors
Jachimowicz, R. D., Beleggia, F., Isensee, J., Velpula, B. B., Goergens, J., Bustos, M. A., Doll, M. A., Shenoy, A., Checa-Rodriguez, C., Wiederstein, J. L., Baranes-Bachar, K., Bartenhagen, C., Hertwig, F., Teper, N., Nishi, T., Schmitt, A., Distelmaier, F., Ludecke, H. J., Albrecht, B., Kruger, M., Schumacher, B., Geiger, T., Hoon, D. S. B., Huertas, P., Fischer, M., Hucho, T., Peifer, M., Ziv, Y., Reinhardt, H. C., Wieczorek, D., Shiloh, Y.
(2019) Cell, 176, 3, 505-519 e22

DNA double-strand break repair pathway choice - from basic biology to clinical exploitation
Jachimowicz, R. D., Goergens, J., Reinhardt, H. C.
(2019) Cell Cycle, 18, 13, 1423-1434

Genomic Amplification of UBQLN4 Is a Prognostic and Treatment Resistance Factor
Kobayashi Y., Bustos M. A. , Shoji Y., Jachimowicz R.D., Shiloh Y., Hoon D.S.B.
Cells. 2022 Oct 21;11(20):3311. doi: 10.3390/cells11203311.

ATM activity in T cells is critical for immune surveillance of lymphoma in vivo
Riabinska, A., Lehrmann, D., Jachimowicz, R. D., Knittel, G., Fritz, C., Schmitt, A., Geyer, A., Heneweer, C., Wittersheim, M., Frenzel, L. P., Torgovnick, A., Wiederstein, J. L., Wunderlich, C. M., Ortmann, M., Paillard, A., Wossmann, W., Borkhardt, A., Burdach, S., Hansmann, M. L., Rosenwald, A., Perner, S., Mall, G., Klapper, W., Merseburg, A., Kruger, M., Grull, H., Persigehl, T., Wunderlich, F. T., Peifer, M., Utermohlen, O., Buttner, R., Beleggia, F., Reinhardt, H. C.
(2020) Leukemia, 34, 3, 771-786

Distinct genetically-determined origins of Myd88/Bcl2-driven aggressive lymphoma rationalize targeted therapeutic intervention strategies
Flümann R., Hansen J., Pelzer B.W., Nieper P., Lohmann T., Kisis I., Riet T.,  Kohlhas V., Nguyen P.H., Peifer M., Abedpour N., Bosco G., Thomas R.K., Kochanek M., Knüfer J., Jonigkeit L., Beleggia F.,  Holzem A., Büttner R., Lohneis P., Meinel J., Ortmann M., Persigehl T., Hallek M., Calado D.P., Chmielewski M., Klein S., Göthert J.R., Chapuy B., Zevnik B., Wunderlich F.T., Tresckow B.v.,  Jachimowicz R.D.,  Melnick A.M., Reinhardt H.C., Knittel G.
Blood Cancer Discov. 2022 Nov 8:BCD- 22-0007. doi: 10.1158/2643-3230.BCD-22-0007.