Research Groups
Genome Stability
Research Interests and Description
Research Interests
DNA repair, genomic instability, RecQ helicases, proteomics.
Description of Research
Our
Group investigates the enzymatic activity and cellular function of RecQ
helicases. This family of DNA unwinding enzymes has attracted considerable
interest in recent years due to their role in the suppression of genome
instability and human diseases. Mutations affecting three of the five human RecQ
helicase genes are linked to distinct genetic disorders associated with
increased incidence of cancer and/or premature aging. Our main focus is RECQ1,
the first RecQ helicase discovered in humans, but also one of the less
characterized in terms of enzymatic activity and function. We apply a
combination of biochemical and structural approaches to characterize the different
oligomeric forms of RECQ1 associated with its DNA unwinding and annealing
activities, and unravel the function of its dual enzymatic activity. Meanwhile,
we exploit new integrated proteomic approaches to describe the protein
composition of macromolecular complexes containing RECQ1 and test how this might
change in a cell cycle and DNA damage dependent fashion. Experiments with human
RECQ1-depleted cells are performed to test the function of RECQ1 and its newly
discovered binding partners in vivo. Recently, we extended the same approaches to other human RecQ enzymes to elucidate the distinct
functions of the five human RecQ helicases in cells. In this regard, the specific
role of the five human helicases in DNA replication is one of our major
interests.
We are also interested in DNA non-homologous end-joining (NHEJ) and in the
analysis of the protein expression profiles of human brain astrocytomas. NHEJ
is one of the two major mechanisms of double strand break repair in cells. We
investigate the order of assembly and the macromolecular interactions of the
NHEJ proteins at the broken DNA ends, and search for novel factors that might
be required for the repair process. Our work on brain astrocytomas aims at the
identification of novel bio-markers for a more accurate classification of tumor
grade. These studies have allowed the identification of a number of proteins
differentially expressed between the indolent low-grade and the highly
infiltrating high-grade form of the tumor, also known as glioblastoma
multiforme.
Recent Publications
Vindigni, A., Hickson, I.D. 2009. RecQ helicases: multiple structures for multiple functions? HFSP Journal 3, 153-164
Pike, A., Shrestha, B., Popuri, V., Burgess-Brown, N., Muzzolini, L.,
Costantini, S., Vindigni, A., Gileadi, O. 2009. Structure of the human
RECQ1 helicase: identification of a putative strand-separation pin.
Proc. Natl. Acad. Sci. USA 106, 1039-1044 [Pubmed link]
Smith, E., Dejsuphong, D., Balestrini, A., Hampel, M., Lenz, C., Vindigni, A., Costanzo, V. 2009. An ATM and ATR dependent checkpoint inactivates spindle assembly by targeting CEP63. Nat. Cell Biol. 11, 278-285 [Pubmed link]
Popuri, V., Bachrati, C.Z., Muzzolini, L., Mosedale, G., Costantini, S., Giacomini, E., Hickson, I.D., Vindigni, A. 2008. The human RecQ helicases, BLM and RECQ1, display distinct DNA substrate specificities. J. Biol. Chem. 283, 17766-17776
Muzzolini,
L., Beuron, F., Patwardhan, A., Popuri, V., Cui, S., Niccolini, B.,
Rappas, M., Freemont, P.S., Vindigni, A. 2007. Different quaternary
structures of human RECQ1 are associated with its dual enzymatic
activity. PLoS Biol. 5, e20 [Pubmed link]
Nijnik, A., Woodbine, L., Marchetti, C., Dawson, S., Lambe, T., Liu, C., Rodrigues, N.P., Crockford, T.L., Cabuy, E., Vindigni, A., Enver, T., Bell, J.I., Slijepcevic, P., Goodnow, C.C., Jeggo, P.A., Cornall, R.J. 2007. DNA repair is limiting for haematopoietic stem cells during ageing. Nature 447, 686-690
