Alessandro Vindigni, Ph.D.
Biochemistry and Molecular Biology
Studies on DNA replication stress, genome stability, and human disease.
Research HighlightsReplication Fork Reversal
Replication fork reversal is rapidly emerging as a pivotal mechanism of replication stress response to cancer chemotherapeutics. This work identifies the first molecular mechanism required to restart replication forks that have reversed upon treatment with DNA topoisomerase I inhibitors. It also provides a new rationale to improve current chemotherapeutic modalities based on the use of DNA replication inhibitors. This article was rated as a “must read” by the Faculty of 1000.
Human RECQ1 promotes restart of replication forks reversed by DNA topoisomerase I inhibition. Berti M, et.al., Nat. Struct. Mol. Biol. 20(3):347-354, 2013. (PMID 23396353).
Replication Stress Response
This work defines new important roles for different human nucleases in replication stress response to cancer chemotherapeutics and opens new avenues to study the link between nucleolytic processing of stalled replication intermediates and chemotherapeutic sensitivity.
DNA2 drives processing and restart of reversed replication forks in human cells. Thangavel S, et.al., . Cell Biol. 208(5):545-562, 2015 (PMID 25733713).
RECQ1 Helicase Structure
This work determines the first DNA complex structures of the human RECQ1 helicase. These structures provide new insight into the RecQ helicase mechanism of DNA tracking, strand separation, and Holliday junction branch migration. This work helps clarify how different RecQ enzymes are uniquely adapted to process potentially recombinogenic DNA structures that arise upon replication stress.
Human RECQ1 helicase-driven DNA unwinding, annealing, and branch migration: insights from DNA complex structures. Pike AC, et.al., Proc. Natl. Acad. Sci. USA. 112(14):4286-4291, 2015. (PMID 25831490).
Our laboratory focuses on the mechanisms of DNA replication and repair, and on the possible strategies to target these mechanisms for cancer treatment. 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. Our work provides a new rationale to design novel molecularly-guided treatments targeting the pathways of replication stress response to cancer chemotherapeutics.
The Architectural Chromatin Factor High Mobility Group A1 Enhances DNA Ligase IV Activity
Influencing DNA Repair
Pellarin I, Arnoldo L, Costantini S, Pegoraro S, Ros G, Penzo C, Triolo G, Demarchi F, Sgarra R, Vindigni A and Manfioletti G
Pubmed | PLoS ONE