Alessandro Vindigni, PhD

Bio

A VindigniI am a Professor of Medicine, Pathology and Immunology at Washington University School of Medicine. I completed my graduate training in Biochemistry and Molecular Biophysics in Italy at the University of Padua and my postdoctoral training at Washington University School of Medicine in Saint Louis. In 2002, I was appointed Group Leader in Genome Stability at the International Centre for Genetic Engineering and Biotechnology (ICGEB), which is an intergovernmental organization aligned with the United Nations system and based in Trieste, Italy. During my tenure at the ICGEB, I gained understanding about the ICGEB mandate as an international organization and I was actively involved in strengthening interactions and new collaborations with member state governments, international organizations and the international scientific community.  In 2011, I relocated to Saint Louis University School of Medicine, where I worked as Professor of Biochemistry and Director of the Graduate Program in Biochemistry and Molecular Biology. Since 2015, I have been serving as Co-Leader of the DNA Metabolism and Repair (DMR) program of the Siteman Cancer Center at Washington University School of Medicine. In 2019, I accepted my current position as Professor of Medicine, Pathology and Immunology at Washington University School of Medicine with the goal of fostering interactions and new collaborations between laboratories working in the closely related areas of DNA damage response, DNA replication and repair, telomere biology, and gene regulation. I have always been fascinated by the mechanisms that bridge DNA and people together!

To view my full profile: https://vindignilab.wustl.edu

Research

Our laboratory focuses on DNA replication and repair, and the roles of these pathways on cancer initiation, progression and response to chemotherapy and immunotherapy. We utilize a unique combination of biochemical, cellular, and electron microscopy approaches to study replication perturbations at single molecule resolutions. Combining these technologies, we identified key pathways by which replication responds to cancer chemotherapeutics and provided new insights on how to target these pathways to increase chemotherapeutic sensitivity (Berti et al., Nat. Struct. Mol. Biol. 2013; Thangavel et al., J. Cell Biol. 2015; Lemacon et al., Nat. Comm. 2017).

More recently, we began studying the adaptive response mechanisms activated by cancer cells to deal with DNA damaging chemotherapy at later time points after drug treatment (Quinet et al., Mol. Cell 2020; Quinet et al., Mol. Cell 2021). These studies identified ssDNA gaps as a central intermediate in the adaptive response to replication stress, especially in the context of homologous-recombination deficient tumors, and led to the proposal of targeting mechanisms of ssDNA gap repair to modulate DNA damaging chemotherapy and PARP inhibitor response.

To learn more about our research: https://vindignilab.wustl.edu

Figure 1a
Figure 1. Representative electron micrograph of a replication fork with internal ssDNA gaps . Red arrows show the location of internal ssDNA gaps located on the daughter strand. The blue arrow shows the location of a ssDNA gap located at the fork junction. D, daughter strand; P, parental strand.

Replication 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 providing the first insight into the molecular steps that drive the resolution of reversed replication forks (Berti et al., Nat. Struct. Mol. Biol. 2013). Shortly thereafter, we identified a second human DNA2- and WRN-dependent mechanism of reversed fork processing and restart (Thangavel et al., J. Cell Biol. 2015). Recently, we uncovered a novel function of breast cancer (BRCA) susceptibility proteins in protecting reversed replication forks from nucleolytic degradation (Lemacon et al., Nat. Comm. 2017). These findings revisit the simplistic view that BRCA protein involvement in replication stress is limited to their role in promoting the homologous recombination-mediated repair of DSBs arising at stalled forks.

Figure 2a
Figure 2. Replication forks facing DNA damaging chemotherapeutics can reverse their course using the fork reversal pathway (Salmon at the bottom) (Berti et al., Nat. Struct. Mol. Biol. 2013). We found that BRCA-deficient cancer cells adapt to treatment with DNA damaging chemotherapeutics by using the PRIMPOL pathway (Salmon jumping out of water) that allows replication forks to bypass blocking DNA damages (rocks in the river) and resume DNA synthesis (Salmon on top) (Quinet et al., Mol. Cell 2020). Image credit: Emma Vidal.

His findings have been highlighted in over 80 peer-reviewed articles published in top scientific journals and led to ongoing collaborations with several groups working at the forefront of the DNA replication, repair and cancer fields.

Recent Publications

  1. Quinet A, Tirman S, Cybulla E, Meroni A, Vindigni A. To skip or not to skip: choosing repriming to tolerate DNA damage. Cell 2021 Feb 18;81(4):649-658.PMID: 33515486
  2. Wood M, Quinet A, Lin YL, Davis AA, Pasero P, Ayala YM,Vindigni A. TDP-43 dysfunction results in R-loop accumulation and DNA replication defects. Cell Sci. 2020 Oct 30;133(20):jcs244129. PMID: 32989039.
  3. Quinet A, Tirman S, Jackson J, Šviković S, Lemaçon D, Carvajal-Maldonado C, González-Acosta D, Vessoni AT, Cybulla E, Wood M, Tavis S, Batista LFZ, Méndez J, Sale JE, Vindigni A. PrimPol-mediated adaptive response suppresses replication fork reversal in BRCA-deficient cells. Cell 2020 Feb 6;77(3):461-474.e9. PMID: 31676232.
  4. Carvajal-Maldonado D, Byrum AK, Jackson J, Wessel S, Lemacon D, Guitton-Sert L, Quinet A, Tirman S, Graziano S, Masson JY, Cortez D, Gonzalo S, Mosammaparast N, Vindigni A. Perturbing cohesin dynamics drives MRE11 nuclease-dependent replication fork slowing. Nucleic Acids Res. 2019 Feb 20;47(3):1294-1310. PMID: 29917110
  5. Quinet A, Lemacon D, Vindigni A. Replication Fork Reversal: Players and Guardians. Mol Cell. 2017 Dec 7;68(5):830-833. PMID: 29220651
  6. Lemaçon D, Jackson J, Quinet A, Brickner JR, Li S, Yazinski S, You Z, Ira G, Zou L, Mosammaparast N, Vindigni A. MRE11 and EXO1 nucleases degrade reversed forks and elicit MUS81-dependent fork rescue in BRCA2-deficient cells. Nat Commun. 2017 Oct 16;8(1):860. PMID: 29038425
  7. Berti M, Vindigni A. Replication stress: getting back on track. Nat Struct Mol Biol. 2016 Feb;23(2):103-9. PMID: 26840898
  8. Thangavel S, Berti M, Levikova M, Pinto C, Gomathinayagam S, Vujanovic M, Zellweger R, Moore H, Lee EH, Hendrickson EA, Cejka P, Stewart S, Lopes M, Vindigni A. DNA2 drives processing and restart of reversed replication forks in human cells. J Cell Biol. 2015 Mar 2;208(5):545-562. PMID: 25733713
  9. Pike AC, Gomathinayagam S, Swuec P, Berti M, Zhang Y, Schnecke C, Marino F, von Delft F, Renault L, Costa A, Gileadi O, Vindigni A. Human RECQ1 helicase-driven DNA unwinding, annealing, and branch migration: insights from DNA complex structures. Proc Natl Acad Sci U S A. 2015 Apr 7;112(14):4286-4291. PMID: 25831490
  10. Berti M, Ray Chaudhuri A, Thangavel S, Gomathinayagam S, Kenig S, Vujanovic M, Odreman F, Glatter T, Graziano S, Mendoza-Maldonado R, Marino F, Lucic B, Biasin V, Gstaiger M, Aebersold R, Sidorova JM, Monnat RJ Jr, Lopes M, Vindigni A. Human RECQ1 promotes restart of replication forks reversed by DNA topoisomerase I inhibition. Nat Struct Mol Biol. 2013 Mar;20(3):347-54. PMID: 23396353.