Domino nucleosome remodeling complexes and histone H2A.V dynamics in transcription and DNA repair (A03)

• Subject Area: General Genetics and Functional Genome Biology
• Term: since 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 213249687

The anti-tumor potency of PARP inhibitors (PARPi) correlates with their “trapping” of PARP proteins on damaged chromatin. We found that the chromatin remodeling enzyme ALC1 (CHD1L) is actively required for the release of DNA damage-recruited PARP2 and that it potentiates the anticancer cell killing properties of clinical PARPi. We will now refine our understanding of ATP-fueled remodeler catalyze PARP2 release by determining how PARPi trap PARP2 using orthogonal biophysical assays, including HDX and live-cell imaging. Further, we will explore the synthetic lethal role of the remodeler HELLS (LSH), which mediates PARPi sensitization, and establish the molecular basis for its allosteric activation.

• DFG Programme: Collaborative Research Centres
• Subproject of: SFB 1064: Chromatin Dynamics
• Applicant Institution: Ludwig-Maximilians-Universität München
• Project Head: Professor Andreas Gerhard Ladurner, Ph.D.