Oncology Division
Alessandro Vindigni

Alessandro Vindigni, PhD

Department of Medicine
Oncology Division
Molecular Oncology
Department of Pathology & Immunology

Research Interests

  • DNA replication and repair
  • Genome stability and tumorigenesis
  • DNA replication stress response
  • DNA damaging chemotherapy


  • 314-273-8612 (office)
  • 314-362-9221 (lab)
  • 314-362-7086 (fax)
  • Division of Oncology
    Campus Box 8056
    Washington University
    660 South Euclid Avenue
    St. Louis, MO 63110
  • Rooms 8844/8848 Clinical Sciences Research Building (lab)


Our group focuses on DNA replication and repair, and the roles of these pathways on cancer initiation, progression and response to chemotherapy and immunotherapy. Aberrant DNA replication is one of the leading causes of mutations and chromosome rearrangements associated with several cancer-related pathologies. At the same time, agents that stall or damage DNA replication forks are widely used for chemotherapy in the attempt to selectively target highly proliferating cancer cells. We use a unique combination of biochemical, cellular, and electron microscopy approaches to study perturbations of replication fork dynamics at single-molecule resolution. Combining these technologies, we identified new pathways by which replication responds to DNA-damaging chemotherapeutics and provided insights on how to target these pathways to increase chemotherapeutic sensitivity.

Replication fork reversal. Fork reversal is a central pathway in the replication stress response to DNA-damaging chemotherapeutics that allows replication forks to cope with DNA lesions by reversing their course. We uncovered a key role of the human RECQ1 helicase in the restart of reversed replication forks. We also found that the fork restart function of RECQ1 is regulated by poly(ADP-ribose) polymerase (PARP1), which suppresses RECQ1 activity until the damage is repaired. Shortly thereafter, we identified a second human DNA2- and WRN-dependent mechanism of reversed fork processing and restart. Collectively, our work provided the first mechanistic insight into how replication forks reverse and restart as a pivotal response to treatment with DNA-damaging chemotherapeutics, and offers new molecular perspectives to potentiate current DNA-damaging chemotherapeutic regimens by targeting fork reversal.

reversed_replication_fork.jpg Representative electron micrograph showing the image of a reversed replication fork. D, daughter strand; P, parental strand; R, reversed arm.

Replication fork protection. Aside from their well-established roles in homologous recombination, BRCA proteins are emerging as key factors required for the maintenance of replication fork stability following chemotherapy. Our group is interested in elucidating the mechanisms that govern fork replication fork protection and recovery in cancer cells, and to understand how to target these mechanisms for the development of new and more effective cancer treatment strategies. To this end, we recently discovered that the main function of BRCA proteins in the context of fork stability is to protect the regressed arms of reversed replication forks from nucleolytic degradation upon drug treatment. We also discovered that extensive fork degradation in BRCA-deficient cells is not a terminal event, because BRCA-mutated cells employ specific fork recovery pathways as a last resort to withstand DNA-damaging chemotherapy. These studies revisit the functions of central homologous recombination factors in DNA replication and are crucial to understanding how targeting fork recovery pathways modulates chemotherapy response.

DNA_replication_events.jpg Representative DNA fiber images of replication forks obtained by fluorescence microscopy. The “pacman” represents the nuclease that degrades the replication fork. Scale bar 15 µM.

Adaptive response to chemotherapeutics. We began to more broadly consider how the replication stress response to DNA-damaging chemotherapeutics changes after treatment with multiple drug doses. Using a novel multiple dose approach, we discovered that cells restrain fork reversal when reversed forks cannot be adequately protected by BRCA proteins. In particular, we found that BRCA1-deficient cells adapt to treatment with multiple doses of platinum-based compounds by suppressing fork reversal and promoting PRIMPOL-repriming, as an alternative strategy to cope with the drug-induced DNA lesions. This effect is generalizable to other conditions of impaired fork reversal (such as loss of the SMARCAL1 translocase or PARP inhibition) and suggests a new strategy to modulate DNA-damaging chemotherapeutic sensitivity by targeting the PRIMPOL pathway. Our goal is to expand this analysis to different DNA-damaging chemotherapeutics and define whether different adaptive response mechanisms are activated at later time points after drug treatment, depending on the nature of the DNA lesion.

Currently, I am the Co-Leader of the DNA Metabolism and Repair (DMR) program of the Siteman Cancer Center at Washington University, which provides a unique platform for scientists working in the closely-related areas of DNA damage response, DNA replication and repair, chromatin biology, and gene regulation.

Lab website: https://vindignilab.wixsite.com/vindignilab