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Alex Pines
Principal Investigator

Pines-Alex

Principal Investigator

  • Department
  • Molecular Genetics
  • Focus area
  • Transcription interfering lesions and cellular homeostasis
Contact  

About

Introduction

Alex Pines received his PhD in Biochemistry in 2005 from the University of Trieste, Italy. He is a cell and molecular biologist with 15+ years’ experience in DNA damage repair pathways, genome stability and age-related diseases. He is a member of the Department of Molecular Genetics since 2015. His research focuses on elucidating the repair mechanisms of transcription interfering lesions and associated diseases.

"We apply a multi-disciplinary approach that involves proteomics, live imaging, and functional genomics, with a particular interest in transcription-associated repair processes."

 Research topic

Recent evidence suggests that persistent DNA damage is associated with ageing and development of neurodegenerative diseases. DNA is susceptible to acquire damage by environmental chemicals, solar radiation and, strikingly, also by molecules produced by the cell’s own metabolism. It was shown that particularly persistent DNA damage that interferes with gene transcription is an important driver of age-related diseases, including progressive neurodegeneration. To counteract the harmful effects of these so-called Transcription-Interfering Lesions (TILs), cells have evolved DNA Damage Response (DDR) that coordinates key cellular processes, including several DNA repair pathways, via post-translational protein modifications (PTMs).
 

The goal of Pines’ research is to reveal the molecular details of DDR to fully comprehend the root causes of TILs driving progressive neurodegeneration. Recent advances in contemporary experimental approaches, such as sophisticated live cell imaging, CRISPR-mediated genome editing, and genome-wide omics have set the scene to take up this challenging research objectives: 

  1. Genome-wide DNA repair distribution
  2. Composition and dynamics of DNA repair complexes during the different stages of the repair process
  3. Cell type-specific responses to TILs
  4. Determine pathophysiological consequences
     

Field(s) of expertise

DNA Damage Response 

Persistent DNA damage and the consequent transcription stress disturb cellular homeostasis. TILs and accompanying transcription stress trigger a strong DNA Damage Response (DDR) that coordinates key cellular processes, mainly via dynamic post-translational protein modifications (PTMs). These PTM- mediated DDR events are thought to target DNA repair, transcription, pre-mRNA splicing and export, chromatin, the translation and protein quality control machineries.

Insight into TIL-induced DDR-associated PTMs changes, and their physiological impact, thus, provide a window to define the fundamental causes of the major age-related neurologic diseases and to develop interventions that alleviate the root cause of ageing-associated morbidity.

Transcription-Coupled Nucleotide Excision Repair 

Transcription-Coupled Nucleotide Excision Repair (TC-NER) represents the major caretaker of the genome to preserve the transcription programs required for normal cellular functioning and is the focus of our research. TC-NER is activated by binding of its critical factors CSA, CSB and UVSSA to stalled RNAPII. CSB is a DNA-dependent ATPase, its translocating activity is essential for recruiting CSA, which is the substrate-adaptor of the Culin4-RING ubiquitin E3 ligase complex (CRL4CSA), and UVSSA, that brings in the broad-spectrum de-ubiquitylation enzyme USP7. An intricate dynamic molecular interplay between CSA-, CSB- and UVSSA containing complexes is required to coordinate the removal of DNA lesion and subsequent transcriptional restart.

 

Following TC-NER factor binding, UVSSA recruits the basal transcription factor TFIIH and XPA to verify the lesion. Subsequently, the single-stranded DNA-binding complex RPA orients the 5’ and 3’ structure-specific endonucleases ERCC1-XPF and XPG to excise the damaged strand, followed by gap filling DNA synthesis and DNA ligation.

Inherited TC-NER-deficiency is associated with serious health threats caused by persistence of RNAPII stalled at endogenously DNA damage, which gives rise to Cockayne syndrome (CS), characterized by cachexia, severe progressive neurological decline and accelerated aging.


Publications

Teaching activities

Alex Pines teaches in the Nanobiology BSc program of Erasmus University and Delft University, where he is course manager and teacher of Journal Club2. 

BMW-MG-studenten-owc

Research Topic

Alex Pines has built up his own, independent, line of research embedded into Prof Wim Vermeulen’s laboratory . As part of the  Molecular Genetics department, with its central research focus on the

"DNA damage response",
Alex Pines’ group closely collaborates with several PIs of the department and with Dr. Arjan F. Theil, consultant scientist of the expertise center ENCORE at ERASMUS MC. Alex Pines has established several national and international collaborations in the DNA repair field, guaranteeing an excellent international network and a scientific embedment of his research.

 

Lately, he has joined forces  with Dr. Willianne I.M. Vonk and Dr. Wilbert Vermeij (Genome Instability & Nutrition, Princess Máxima Center (PMC) to study DNA damage-associated protein quality control in neurodegeneration.