Analyse von Chromosomen

Analyse von Chromosomen
Untersuchung der Replikation

Untersuchung der Replikation
Proteinanalyse

Proteinanalyse
Projektplanung

Projektplanung

Homologous Recombination and Genomic Instability

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PD Dr. Kerstin Borgmann Dipl.-Biol.
Dr. Ann Christin Parplys, Dipl.-Biol.
Dr. Yvonne Goy, Strahlentherapie-Ärztin
Britta Riepen, MTA
Alexandra Zielinski, MTA
Felix Meyer, Dipl.Biol. PhD Stud.
Patrick Dinkelborg, Stud. Med.
Johanna Rieckhoff, Stud. Med.
Jonas Willmann, Stud. Med.
Antonia Niecke, BSc. Stud.
Jordi Carstens, BSc. Stud.

Topic 1 — Targeting of homologous recombination in triple negative breast cancer

The aim of this project is to identify tumors defective in Homologous recombination and checkpoint signaling to intensify future radiotherapy by specific inhibitors against PARP1 and CHK1. Homologous recombination (HR) comprises a series of interrelated pathways that function in the repair of DNA double strand breaks (DSBs) and interstrand crosslinks (ICLs). In addition, HR provides critical support for the recovery of stalled replication forks during DNA replication, contributing to tolerance of DNA damage. The inability to properly repair complex DNA damage and resolve DNA replication stress leads to genomic instability and contributes to cancer development. So far, little is known about the effect of RAD51 overexpression on genomic instability caused by replication errors and Intra-S-Phase checkpoint signaling.

Fig. 1
Fig. 1

Figure 1: (A) RAD51 expression various substantially in breast cancer cell lines. (B) High RAD51 expression leads to a reduced HR frequency in the plasmid reconstruction assay.

Selected recent papers

  • Tennstedt P, Fresow R, Simon R, Marx A, Terracciano L, Petersen C, Sauter G, Dikomey E, Borgmann K. RAD51 overexpression is a negative prognostic marker for colorectal adenocarcinoma. Int J Cancer 2013; 132:2118-26.
  • Pfaffle HN, Wang M, Gheorghiu L, Ferraiolo N, Greninger P, Borgmann K, Settleman J, Benes CH, Sequist LV, Zou L, Willers H, EGFR-Activating Mutations Correlate with a Fanconi Anemia-like Cellular Phenotype That Includes PARP Inhibitor Sensitivity, Cancer Res 2013; 73:6254-6263.
  • Raabe A, Derda K, Reuther S, Szymczak S, Borgmann K, Hoeller U, Ziegler A, Petersen C, Dikomey E. Association of single nucleotide polymorphisms in the genes ATM, GSTP1, SOD2, TGFB1, XPD and XRCC1 with risk of severe erythema after breast conserving radiotherapy. Radiat Oncol 2012 26;7:65.
  • Kachnic LA, Li L, Fournier L, Ferraiolo N, Dahm-Daphi J, Borgmann K, Willers H. FANCD2 but not FANCA promotes cellular resistance to type II topoisomerase poisons. Cancer Lett. 2011; 305:86-93.
  • Borgmann K, Raabe A, Reuther S, Szymczak S, Schlomm T, Isbarn H, Gomolka M, Busjahn A, Bonin M, Ziegler A, Dikomey E. The potential role of G2- but not of G0-radiosensitivity for predisposition of prostate cancer. Radiother Oncol 2010; 96:19-24.
  • Storch K, Eke I, Borgmann K, Krause M, Richter C, Becker K, Schröck E, Cordes N. Three-dimensional cell growth confers radioresistance by chromatin density modification. Cancer Res 2010; 70:3925-34.
Grants
BMU Grant No. 3610S30016, BMBF Grant No. 02NUK032, Universität Hamburg, Werner Otto Stiftung

Topic 2 — Genomic instability as a marker for early onset breast cancers

Grants
BMU Grant No. 3610S30016, BMBF Grant No. 02NUK032, Universität Hamburg, Werner Otto Stiftung

The aim of this project is to better understand the molecular and biological mechanisms leading to early onset breast cancers. Therefore we are investigating the functional impact of PALB2, BRCA1 and BRCA2 as well as ABRAXAS mutations on DNA replication, DNA damage checkpoint functions and genomic instability. Maintenance of genomic stability, especially in S/G2 phase is controlled by the DNA repair mechanism Homologous Recombination (HR). De-regulation of this pathway leads to failed DNA repair at replication forks which may result in increased genomic instability finally causing cancer. PALB2 is known to regulate HR via RAD51 by binding to BRCA1 and mediating the interaction between BRCA1 and BRCA2. Defects in the PALB2 and other HR genes have been associated with cancer susceptibility. For PALB2 and other HR proteins is was shown that a mutation in one of these genes leads to a up to ten-fold increase of breast cancer risk. In parallel to the analysis of mutation carriers the hypothesis that defects in replication processes itself lead to early onset breast cancers will be analyzed.

Fig. 2
Fig. 2

Figure 2: A heterozygote defect in PALB2 perturbs replication processes, visible in a reduced replication rate (A) increased origin firing (B) compared to non-carriers, leading to a reduced distance between neighbored origins resulting in increased genomic instability.

Selected recent papers

  • Parplys AC, Kratz K, Speed MC, Leung SG, Schild D, Wiese C. RAD51AP1-deficiency in vertebrate cells impairs DNA replication. DNA Repair. 2014; 24:1568-7864.
  • Nikkilä J, Parplys AC, Pylkäs K, Bose M, Huo Y, Borgmann K, Rapakko K, Nieminen P, Xia B, Pospiech H, Winqvist R. Heterozygous mutations in PALB2 cause DNA replication and damage response defects. Nat Commun. 2013; 4:2578.
  • Parplys AC, Petermann E, Petersen C, Dikomey E, Borgmann K. DNA damage by X-rays and their impact on replication processes.Radiother Oncol. 2012; 102:466-71.

Grants
Forschungsförderung Medizin des UKE, Werner Otto Stiftung

Grants
Forschungsförderung Medizin des UKE, Werner Otto Stiftung