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IGM-CNR, Via Abbiategrasso, 207 - 27100 Pavia, Italy
tel: +39-0382-546339
fax: +39-0382-422286
E-mail: sabbioneda igm.cnr.it
http://www.igm.cnr.it/
Curriculum vitae
Qualifications
PhD: 2004: University of Milan, Italy (in Genetics and Molecular Sciences)
BSc: 2001: University of Milan (in Biological Sciences)
Employment and Affiliations
Researcher: Oct. 2011-date, Istituto di Genetica Molecolare, CNR
Postdoctoral Fellow: 2005-2011, Genome Damage and Stability Centre, University of Sussex, UK
Postdoctoral Fellow: 2005, Dept. of Biomolecular Sciences and Biotechnology, University of Milan
Research Activities
DNA replication is a highly processive and accurate process, but DNA damage is an extraordinary challenge and if left unrepaired can lead to increased mutagenesis, replication fork stalling and subsequent cell death. At the organism level these deficiencies can lead to cancerogenesis, neurodegeneration and immune defect. A tolerance mechanism called Post Replication Repair (PRR) can efficiently bypass unrepaired damage and allows completion of replication. PRR can bypass the damage either using translesion synthesis (TLS) polymerases or a recombination-like mechanism called “template switch”. TLS utilizes specialized DNA polymerases to replicate across damaged bases thanks to their open catalytic site that can accommodate a highly distorted template.
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Most of the TLS polymerases belong to the Y family including polymerase eta, iota, kappa and Rev1 along with the B class polymerase zeta. Due to their open ca talytic site TLS polymerases are error prone in replicating undamaged DNA and it is therefore crucial to control their recruitment during replication to avoid increased mutagenesis and genome instability. Polη has the unique capability to replicate across the major UV adduct, cyclobutane pyrimidine dimers (CPD), in an error free manner. In its absence the bypass is carried out by the other polymerases with different degrees of accuracy leading to a 40 fold increase in mutation frequency. Incorporation of the wrong nucleotides in front of the lesion it is thought to be the cause of such increased mutagenesis that could then result, in the long term, in genome instability, one of the hallmarks of cancer. A deficiency in polη is the cause of the genetic disease XPV. XPV patients present with abnormal pigmentation of the skin and are highly prone to sunlight-induced skin cancers, such as basal and squamous cell carcinomas and malignant melanomas.
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The main focus of my lab is to characterize how polη is regulated by post-translational modifications (Ubiquitination, phosphorylation and SUMO) , in the context of the cellular repair mechanisms and DNA damage checkpoints. We tackle these questions via a multidisciplinary approach ranging from cell biology to protein biochemistry in human cell lines. Work in the lab is aimed to provide insights into the way that polη assists in the maintenance of genome stability as a barrier for cancer development, potentially providing diagnostic biomarkers for atypical XPV diagnosis and, in the long-term, hopefully contribute to the design of rational cancer therapies.
2012-2016 Marie Curie Career Integration Grant (7th framework program) – “Regulation of pol? by phosphorylation, ubiquitination and SUMOylation”
2013-2018 AIRC Start-Up Grant – “Effects on genome stability of polymerase eta regulation by the Ubiquitin and SUMO pathways”.
Publications
1: Maffia A, Ranise C, Sabbioneda S. From R-Loops to G-Quadruplexes: Emerging
New Threats for the Replication Fork. Int J Mol Sci. 2020 Feb 22;21(4):1506.
doi: 10.3390/ijms21041506. PMID: 32098397; PMCID: PMC7073102.
2: Cipolla L, Bertoletti F, Maffia A, Liang CC, Lehmann AR, Cohn MA, Sabbioneda
S. UBR5 interacts with the replication fork and protects DNA replication from
DNA polymerase ? toxicity. Nucleic Acids Res. 2019 Dec 2;47(21):11268-11283.
doi: 10.1093/nar/gkz824. PMID: 31586398; PMCID: PMC6868395.
3: Belloni E, Di Matteo A, Pradella D, Vacca M, Wyatt CDR, Alfieri R, Maffia A,
Sabbioneda S, Ghigna C. Gene Expression Profiles Controlled by the Alternative
Splicing Factor Nova2 in Endothelial Cells. Cells. 2019 Nov 23;8(12):1498. doi:
10.3390/cells8121498. PMID: 31771184; PMCID: PMC6953062.
4: Riva V, Garbelli A, Casiraghi F, Arena F, Trivisani CI, Gagliardi A, Bini L,
Schroeder M, Maffia A, Sabbioneda S, Maga G. Novel alternative ribonucleotide
excision repair pathways in human cells by DDX3X and specialized DNA
polymerases. Nucleic Acids Res. 2020 Nov 18;48(20):11551-11565. doi:
10.1093/nar/gkaa948. PMID: 33137198; PMCID: PMC7672437.
5: González Besteiro MA, Calzetta NL, Loureiro SM, Habif M, Bétous R, Pillaire
MJ, Maffia A, Sabbioneda S, Hoffmann JS, Gottifredi V. Chk1 loss creates
replication barriers that compromise cell survival independently of excess
origin firing. EMBO J. 2019 Aug 15;38(16):e101284. doi:
10.15252/embj.2018101284. Epub 2019 Jul 11. PMID: 31294866; PMCID: PMC6694221.
6: Muzi-Falconi M, Sabbioneda S, Plevani P, Foiani M. Sometimes size does
matter. Eur J Cancer. 2003 Jul;39(10):1337-8. doi:
10.1016/s0959-8049(03)00127-8. PMID: 12826033.
7: Besio R, Garibaldi N, Leoni L, Cipolla L, Sabbioneda S, Biggiogera M, Mottes
M, Aglan M, Otaify GA, Temtamy SA, Rossi A, Forlino A. Cellular stress due to
impairment of collagen prolyl hydroxylation complex is rescued by the chaperone
4-phenylbutyrate. Dis Model Mech. 2019 Jun 20;12(6):dmm038521. doi:
10.1242/dmm.038521. PMID: 31171565; PMCID: PMC6602311.
8: Cea V, Cipolla L, Sabbioneda S. Replication of Structured DNA and its
implication in epigenetic stability. Front Genet. 2015 Jun 16;6:209. doi:
10.3389/fgene.2015.00209. PMID: 26136769; PMCID: PMC4468945.
9: Cipolla L, Maffia A, Bertoletti F, Sabbioneda S. The Regulation of DNA Damage
Tolerance by Ubiquitin and Ubiquitin-Like Modifiers. Front Genet. 2016 Jun
13;7:105. doi: 10.3389/fgene.2016.00105. Erratum in: Front Genet. 2016 Sep
30;7:184. PMID: 27379156; PMCID: PMC4904029.
10: Lehmann AR, Niimi A, Ogi T, Brown S, Sabbioneda S, Wing JF, Kannouche PL,
Green CM. Translesion synthesis: Y-family polymerases and the polymerase switch.
DNA Repair (Amst). 2007 Jul 1;6(7):891-9. doi: 10.1016/j.dnarep.2007.02.003.
Epub 2007 Mar 23. PMID: 17363342.
11: Besio R, Iula G, Garibaldi N, Cipolla L, Sabbioneda S, Biggiogera M, Marini
JC, Rossi A, Forlino A. 4-PBA ameliorates cellular homeostasis in fibroblasts
from osteogenesis imperfecta patients by enhancing autophagy and stimulating
protein secretion. Biochim Biophys Acta Mol Basis Dis. 2018 May;1864(5 Pt
A):1642-1652. doi: 10.1016/j.bbadis.2018.02.002. Epub 2018 Feb 10. PMID:
29432813; PMCID: PMC5908783.
12: Bertoletti F, Cea V, Liang CC, Lanati T, Maffia A, Avarello MDM, Cipolla L,
Lehmann AR, Cohn MA, Sabbioneda S. Phosphorylation regulates human pol?
stability and damage bypass throughout the cell cycle. Nucleic Acids Res. 2017
Sep 19;45(16):9441-9454. doi: 10.1093/nar/gkx619. PMID: 28934491; PMCID:
PMC5766190.
13: Mentegari E, Crespan E, Bavagnoli L, Kissova M, Bertoletti F, Sabbioneda S,
Imhof R, Sturla SJ, Nilforoushan A, Hübscher U, van Loon B, Maga G.
Ribonucleotide incorporation by human DNA polymerase ? impacts translesion
synthesis and RNase H2 activity. Nucleic Acids Res. 2017 Mar 17;45(5):2600-2614.
doi: 10.1093/nar/gkw1275. PMID: 27994034; PMCID: PMC5389505.
14: Kanu N, Zhang T, Burrell RA, Chakraborty A, Cronshaw J, DaCosta C, Grönroos
E, Pemberton HN, Anderton E, Gonzalez L, Sabbioneda S, Ulrich HD, Swanton C,
Behrens A. RAD18, WRNIP1 and ATMIN promote ATM signalling in response to
replication stress. Oncogene. 2016 Jul 28;35(30):4009-19. doi:
10.1038/onc.2015.427. Epub 2015 Nov 9. Erratum in: Oncogene. 2016 Jul
28;35(30):4020. PMID: 26549024; PMCID: PMC4842010.
15: Zlatanou A, Sabbioneda S, Miller ES, Greenwalt A, Aggathanggelou A, Maurice
MM, Lehmann AR, Stankovic T, Reverdy C, Colland F, Vaziri C, Stewart GS. USP7 is
essential for maintaining Rad18 stability and DNA damage tolerance. Oncogene.
2016 Feb 25;35(8):965-76. doi: 10.1038/onc.2015.149. Epub 2015 May 11. PMID:
25961918.
16: Harley ME, Murina O, Leitch A, Higgs MR, Bicknell LS, Yigit G, Blackford AN,
Zlatanou A, Mackenzie KJ, Reddy K, Halachev M, McGlasson S, Reijns MAM, Fluteau
A, Martin CA, Sabbioneda S, Elcioglu NH, Altmüller J, Thiele H, Greenhalgh L,
Chessa L, Maghnie M, Salim M, Bober MB, Nürnberg P, Jackson SP, Hurles ME,
Wollnik B, Stewart GS, Jackson AP. TRAIP promotes DNA damage response during
genome replication and is mutated in primordial dwarfism. Nat Genet. 2016
Jan;48(1):36-43. doi: 10.1038/ng.3451. Epub 2015 Nov 23. PMID: 26595769; PMCID:
PMC4697364.
17: Kanu N, Zhang T, Burrell RA, Chakraborty A, Cronshaw J, DaCosta C, Grönroos
E, Pemberton HN, Anderton E, Gonzalez L, Sabbioneda S, Ulrich HD, Swanton C,
Behrens A. RAD18, WRNIP1 and ATMIN promote ATM signalling in response to
replication stress. Oncogene. 2016 Jul 28;35(30):4020. doi:
10.1038/onc.2015.500. Epub 2016 Jun 27. Erratum for: Oncogene. 2016 Jul
28;35(30):4009-19. PMID: 27345393.
18: Bienko M, Green CM, Sabbioneda S, Crosetto N, Matic I, Hibbert RG, Begovic
T, Niimi A, Mann M, Lehmann AR, Dikic I. Regulation of translesion synthesis DNA
polymerase eta by monoubiquitination. Mol Cell. 2010 Feb 12;37(3):396-407. doi:
10.1016/j.molcel.2009.12.039. PMID: 20159558.
19: Göhler T, Sabbioneda S, Green CM, Lehmann AR. ATR-mediated phosphorylation
of DNA polymerase ? is needed for efficient recovery from UV damage. J Cell
Biol. 2011 Jan 24;192(2):219-27. doi: 10.1083/jcb.201008076. Epub 2011 Jan 17.
PMID: 21242293; PMCID: PMC3172178.
20: Mari PO, Verbiest V, Sabbioneda S, Gourdin AM, Wijgers N, Dinant C, Lehmann
AR, Vermeulen W, Giglia-Mari G. Influence of the live cell DNA marker DRAQ5 on
chromatin-associated processes. DNA Repair (Amst). 2010 Jul 1;9(7):848-55. doi:
10.1016/j.dnarep.2010.04.001. Epub 2010 May 2. PMID: 20439168.
21: Sabbioneda S, Green CM, Bienko M, Kannouche P, Dikic I, Lehmann AR.
Ubiquitin-binding motif of human DNA polymerase eta is required for correct
localization. Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):E20; author reply
E21. doi: 10.1073/pnas.0812744106. PMID: 19240217; PMCID: PMC2650340.
22: Niimi A, Brown S, Sabbioneda S, Kannouche PL, Scott A, Yasui A, Green CM,
Lehmann AR. Regulation of proliferating cell nuclear antigen ubiquitination in
mammalian cells. Proc Natl Acad Sci U S A. 2008 Oct 21;105(42):16125-30. doi:
10.1073/pnas.0802727105. Epub 2008 Oct 9. PMID: 18845679; PMCID: PMC2571029.
23: Sabbioneda S, Gourdin AM, Green CM, Zotter A, Giglia-Mari G, Houtsmuller A,
Vermeulen W, Lehmann AR. Effect of proliferating cell nuclear antigen
ubiquitination and chromatin structure on the dynamic properties of the Y-family
DNA polymerases. Mol Biol Cell. 2008 Dec;19(12):5193-202. doi:
10.1091/mbc.e08-07-0724. Epub 2008 Sep 17. PMID: 18799611; PMCID: PMC2592664.
24: Sabbioneda S, Minesinger BK, Giannattasio M, Plevani P, Muzi-Falconi M,
Jinks-Robertson S. The 9-1-1 checkpoint clamp physically interacts with polzeta
and is partially required for spontaneous polzeta-dependent mutagenesis in
Saccharomyces cerevisiae. J Biol Chem. 2005 Nov 18;280(46):38657-65. doi:
10.1074/jbc.M507638200. Epub 2005 Sep 15. PMID: 16169844.
25: Sabbioneda S, Bortolomai I, Giannattasio M, Plevani P, Muzi-Falconi M. Yeast
Rev1 is cell cycle regulated, phosphorylated in response to DNA damage and its
binding to chromosomes is dependent upon MEC1. DNA Repair (Amst). 2007 Jan
4;6(1):121-7. doi: 10.1016/j.dnarep.2006.09.002. Epub 2006 Oct 10. PMID:
17035102.
26: Giannattasio M, Sabbioneda S, Minuzzo M, Plevani P, Muzi-Falconi M.
Correlation between checkpoint activation and in vivo assembly of the yeast
checkpoint complex Rad17-Mec3-Ddc1. J Biol Chem. 2003 Jun 20;278(25):22303-8.
doi: 10.1074/jbc.M301260200. Epub 2003 Apr 2. PMID: 12672803.
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